Ion channel modulators and methods of use

ABSTRACT

In general, the invention relates to novel 4-phenylpyrimidine compounds useful as ion channel modulators. It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are useful as inhibitors of voltage-gated sodium channels and/or calcium channels for the treatment of pain.

CLAIM OF PRIORITY

This application claims priority to U.S. Provisional Patent Application Nos. 60/624,718; 60/624,716; and 60/624,800, all of which were filed on Nov. 3, 2004. The entire contents of the aforementioned applications are incorporated in their entirety.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors of ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

Na channels are central to the generation of action potentials in all excitable cells such as neurons and myocytes. They play key roles in excitable tissue including brain, smooth muscles of the gastrointestinal tract, skeletal muscle, the peripheral nervous system, spinal cord and airway. As such, they play key roles in a variety of disease states such as epilepsy (See, Moulard, B. and D. Bertrand (2002) “Epilepsy and sodium channel blockers” Expert Opin. Ther. Patents 12(1): 85-91)), pain (See, Waxman, S. G., S. Dib-Hajj, et al. (1999) “Sodium channels and pain” Proc Natl Aced Sci USA 96(14): 7635-9 and Waxman, S. G., T. R. Cummins, et al. (2000) “Voltage-gated sodium channels and the molecular pathogenesis of pain: a review” J Rehabil Res Dev 37(5): 517-28), myotonia (See, Meola, G. and V. Sansone (2000) “Therapy in myotonic disorders and in muscle channelopathies” Neurol Sci 21(5): S953-61 and Mankodi, A. and C. A. Thornton (2002) “Myotonic syndromes” Curr Opin Neurol 15(5): 545-52), ataxia (See, Meister, M. H., J. A. Kearney, et al. (2002) “Mutations of voltage-gated sodium channels in movement disorders and epilepsy” Novartis Found Symp 241: 72-81), multiple sclerosis (See, Black, J. A., S. Dib-Hajj, et al. (2000) “Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis” Proc Natl Acad Sci USA 97(21): 11598-602, and Renganathan, M., M. Gelderblom, et al. (2003) “Expression of Na(v)1.8 sodium channels perturbs the firing patterns of cerebellar purkinje cells” Brain Res 959(2): 235-42), irritable bowel (See, Su, X., R. E. Wachtel, et al. (1999) “Capsaicin sensitivity and voltage-gated sodium currents in colon sensory neurons from rat dorsal root ganglia” Am J Physiol 277(6 Pt 1): 01180-8, and Laird, J. M., V. Souslova, et al. (2002) “Deficits in visceral pain and referred hyperalgesia in Nav1.8 (SNS/PN3)-null mice” J Neurosci 22(19): 8352-6), urinary incontinence and visceral pain (See, Yoshimura, N., S. Seki, et al. (2001) “The involvement of the tetrodotoxin-resistant sodium channel Na(v)1.8 (PN3/SNS) in a rat model of visceral pain” J Neurosci 21(21): 8690-6), as well as an array of psychiatry dysfunctions such as anxiety and depression (See, Hurley, S. C. (2002) “Lamotrigine update and its use in mood disorders” Ann Pharmacother 36(5): 860-73).

Voltage gated Na channels comprise a gene family consisting of 9 different subtypes (NaV1.1-NaV1.9). As shown in Table A, these subtypes show tissue specific localization and functional differences (See, Goldin, A. L. (2001) “Resurgence of sodium channel research” Annu Rev Physiol 63: 871-94). Three members of the gene family (NaV1.8, 1.9, 1.5) are resistant to block by the well-known Na channel blocker TTX, demonstrating subtype specificity within this gene family. Mutational analysis has identified glutamate 387 as a critical residue for TTX binding (See, Nada, M., H. Suzuki, et al. (1989) “A single point mutation confers tetrodotoxin and saxitoxin insensitivity on the sodium channel II” FEBS Lett 259(1): 213-6).

TABLE A (Abbreviations: CNS = central nervous system, PNS = peripheral nervous sytem, DRG = dorsal root ganglion, TG = Trigeminal ganglion): Na isoform Tissue TTX IC50 Indications NaV1.1 CNS, PNS 10 nM Pain, Epilepsy, soma of neurodegeneration neurons NaV1.2 CNS, high in 10 nM Neurodegeneration axons Epilepsy NaV1.3 CNS, 15 nM Pain embryonic, injured nerves NaV1.4 Skeletal 25 nM Myotonia muscle NaV1.5 Heart 2 μM Arrythmia, long QT NaV1.6 CNS 6 nM Pain, movement disorders widespread, most abuntant NaV1.7 PNS, DRG, 25 nM Pain, Neuroendocrine terminals disorders neuroendocrine NaV1.8 PNS, small >50 μM Pain neurons in DRG & TG NaV1.9 PNS, small 1 μM Pain neurons in DRG & TG

In general, voltage-gated sodium channels (NaVs) are responsible for initiating the rapid upstroke of action potentials in excitable tissue in nervous system, which transmit the electrical signals that compose and encode normal and aberrant pain sensations. Antagonists of NaV channels can attenuate these pain signals and are useful for treating a variety of pain conditions, including but not limited to acute, chronic, inflammatory, and neuropathic pain. Known NaV antagonists, such as TTX, lidocaine (See, Mao, J. and L. L. Chen (2000) “Systemic lidocaine for neuropathic pain relief” Pain 87(1): 7-17.), bupivacaine, phenyloin (See, Jensen, T. S. (2002) “Anticonvulsants in neuropathic pain: rationale and clinical evidence” Eur J Pain 6 (Suppl A): 61-8), lamotrigine (See, Rozen, T. D. (2001) “Antiepileptic drugs in the management of cluster headache and trigeminal neuralgia” Headache 41 Suppl 1: S25-32 and Jensen, T. S. (2002) “Anticonvulsants in neuropathic pain: rationale and clinical evidence” Eur J Pain 6 (Suppl A): 61-8.), and carbamazepine (See, Backonja, M. M. (2002) “Use of anticonvulsants for treatment of neuropathic pain” Neurology 59(5 Suppl 2): S14-7), have been shown to be useful attenuating pain in humans and animal models.

Hyperalgesia (extreme sensitivity to something painful) that develops in the presence of tissue injury or inflammation reflects, at least in part, an increase in the excitability of high-threshold primary afferent neurons innervating the site of injury. Voltage sensitive sodium channels activation is critical for the generation and propagation of neuronal action potentials. There is a growing body of evidence indicating that modulation of NaV currents is an endogenous mechanism used to control neuronal excitability (See, Goldin, A. L. (2001) “Resurgence of sodium channel research” Annu Rev Physiol 63: 871-94.). Several kinetically and pharmacologically distinct voltage-gated sodium channels are found in dorsal root ganglion (DRG) neurons. The TTX-resistant current is insensitive to micromolar concentrations of tetrodotoxin, and displays slow activation and inactivation kinetics and a more depolarized activation threshold when compared to other voltage-gated sodium channels. TTX-resistant sodium currents are primarily restricted to a subpopulation of sensory neurons likely to be involved in nociception. Specifically, TTX-resistant sodium currents are expressed almost exclusively in neurons that have a small cell-body diameter and give rise to small-diameter slow-conducting axons and that are responsive to capsaicin. A large body of experimental evidence demonstrates that TTX-resistant sodium channels are expressed on C-fibers and are important in the transmission of nociceptive information to the spinal cord.

Intrathecal administration of antisense oligo-deoxynucleotides targeting a unique region of the TTX-resistant sodium channel (NaV1.8) resulted in a significant reduction in PGE₂induced hyperalgesia (See, Khasar, S. G., M. S. Gold, et al. (1998) “A tetrodotoxin-resistant sodium current mediates inflammatory pain in the rat” Neurosci Lett 256(1): 17-20). More recently, a knockout mouse line was generated by Wood and colleagues, which lacks functional NaV1.8. The mutation has an analgesic effect in tests assessing the animal's response to the inflammatory agent carrageenan (See, Akopian, A. N., V. Souslova, et al. (1999) “The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways” Nat Neurosci 2(6): 541-8.). In addition, deficit in both mechano- and thermoreception were observed in these animals. The analgesia shown by the Nav1.8 knockout mutants is consistent with observations about the role of TTX-resistant currents in nociception.

Immunohistochemical, in-situ hybridization and in-vitro electrophysiology experiments have all shown that the sodium channel NaV1.8 is selectively localized to the small sensory neurons of the dorsal root ganglion and trigeminal ganglion (See, Akopian, A. N., L. Sivilotti, et al. (1996) “A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons” Nature 379(6562): 257-62.). The primary role of these neurons is the detection and transmission of nociceptive stimuli. Antisense and immunohistochemical evidence also supports a role for NaV1.8 in neuropathic pain (See, Lai, J., M. S. Gold, et al. (2002) “Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8” Pain 95(1-2): 143-52, and Lai, J., J. C. Hunter, et al. (2000) “Blockade of neuropathic pain by antisense targeting of tetrodotoxin-resistant sodium channels in sensory neurons” Methods Enzymol 314: 201-13.). NaV1.8 protein is upregulated along uninjured C-fibers adjacent to the nerve injury. Antisense treatment prevents the redistribution of NaV1.8 along the nerve and reverses neuropathic pain. Taken together the gene-knockout and antisense data support a role for NaV1.8 in the detection and transmission of inflammatory and neuropathic pain.

In neuropathic pain states, there is a remodeling of Na channel distribution and subtype. In the injured nerve, expression of NaV1.8 and NaV1.9 are greatly reduced whereas expression of the TTX sensitive subunit NaV1.3 is 5-10 fold upregulated (See, Dib-Hajj, S. D., J. Fjell, et al. (1999) “Plasticity of sodium channel expression in DRG neurons in the chronic constriction injury model of neuropathic pain.” Pain 83(3): 591-600.) The timecourse of the increase in NaV1.3 parallels the appearance of allodynia in animal models subsequent to nerve injury. The biophysics of the NaV1.3 channel is distinctive in that it shows very fast repriming after inactivation following an action potential. This allows for sustained rates of high firing as is often seen in the injured nerve (See, Cummins, T. R., F. Aglieco, et al. (2001) “Nav1.3 sodium channels: rapid repriming and slow closed-state inactivation display quantitative differences after expression in a mammalian cell line and in spinal sensory neurons” J Neurosci 21(16): 5952-61.). NaV1.3 is expressed in the central and peripheral systems of man. NaV1.9 is similar to NaV1.8 as it is selectively localized to small sensory neurons of the dorsal root ganglion and trigeminal ganglion (See. Fang, X., L. Djouhri, et al. (2002). “The presence and role of the tetrodotoxin-resistant sodium channel Na(v)1.9 (NaN) in nociceptive primary afferent neurons.” J Neurosci 22(17): 7425-33.). It has a slow rate of inactivation and left-shifted voltage dependence for activation (See, Dib-Hajj, S., J. A. Black, et al. (2002) “NaN/Nav1.9: a sodium channel with unique properties” Trends Neurosci 25(5): 253-9.). These two biophysical properties allow NaV1.9 to play a role in establishing the resting membrane potential of nociceptive neurons. The resting membrane potential of NaV1.9 expressing cells is in the −55 to −50 mV range compared to −65 mV for most other peripheral and central neurons. This persistent depolarization is in large part due to the sustained low-level activation of NaV1.9 channels. This depolarization allows the neurons to more easily reach the threshold for firing action potentials in response to nociceptive stimuli. Compounds that block the NaV1.9 channel may play an important role in establishing the set point for detection of painful stimuli. In chronic pain states, nerve and nerve ending can become swollen and hypersensitive exhibiting high frequency action potential firing with mild or even no stimulation. These pathologic nerve swellings are termed neuromas and the primary. Na channels expressed in them are NaV 1.8 and NaV 1.7 (See, Kretschmer, T., L. T. Happel, et al. (2002) “Accumulation of PN1 and PN3 sodium channels in painful human neuroma-evidence from immunocytochemistry” Acta Neurochir (Wien) 144(8): 803-10; discussion 810.). NaV1.6 and NaV1.7 are also expressed in dorsal root ganglion neurons and contribute to the small TTX sensitive component seen in these cells. NaV1.7 in particular may therefore be a potential pain target in addition to its role in neuroendocrine excitability (See, Klugbauer, N., L. Lacinova, et al. (1995) “Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells” Embo J 14(6): 1084-90).

NaV1.1 (See, Sugawara, T., E. Mazaki-Miyazaki, et al. (2001) “Nav1.1 mutations cause febrile seizures associated with afebrile partial seizures.” Neurology 57(4): 703-5.) and NaV 1.2 (See, Sugawara, T., Y. Tsurubuchi, et al. (2001) “A missense mutation of the Na+ channel alpha II subunit gene Na(v)1.2 in a patient with febrile and afebrile seizures causes channel dysfunction” Proc Natl Acad Sci USA 98(11): 6384-9) have been linked to epilepsy conditions including febrile seizures. There are over 9 genetic mutations in NaV1.1 associated with febrile seizures (See, Meisler, M. H., J. A. Kearney, et al. (2002) “Mutations of voltage-gated sodium channels in movement disorders and epilepsy” Novartis Found Symp 241: 72-81)

Antagonists for NaV1.5 have been developed and used to treat cardiac arrhythmias. A gene defect in NaV1.5 that produces a larger noninactivating component to the current has been linked to long QT in man and the orally available local anesthetic mexilitine has been used to treat this condition (See, Wang, D. W., K. Yazawa, et al. (1997) “Pharmacological targeting of long QT mutant sodium channels.” J Clin Invest 99(7): 1714-20).

Several Na channel blockers are currently used or being tested in the clinic to treat epilepsy (See, Moulard, B. and D. Bertrand (2002) “Epilepsy and sodium channel blockers” Expert Opin. Ther. Patents 12(1): 85-91.); acute (See, Wiffen, P., S. Collins, et al. (2000) “Anticonvulsant drugs for acute and chronic pain” Cochrane Database Syst Rev 3), chronic (See, Wiffen, P., S. Collins, et al. (2000) “Anticonvulsant drugs for acute and chronic pain” Cochrane Database Syst Rev 3, and Guay, D. R. (2001) “Adjunctive agents in the management of chronic pain” Pharmacotherapy 21(9): 1070-81), inflammatory (See, Gold, M. S. (1999) “Tetrodotoxin-resistant Na+ currents and inflammatory hyperalgesia.” Proc Natl Acad Sci USA 96(14): 7645-9), and neuropathic pain (See, Strichartz, G. R., Z. Zhou, et al. (2002) “Therapeutic concentrations of local anaesthetics unveil the potential role of sodium channels in neuropathic pain” Novartis Found Symp 241: 189-201, and Sandner-Kiesling, A., G. Rumpold Seitlinger, et al. (2002) “Lamotrigine monotherapy for control of neuralgia after nerve section” Acta Anaesthesiol Scand 46(10): 1261-4); cardiac arrhythmias (See, An, R. H., R. Bangalore, et al. (1996) “Lidocaine block of LQT-3 mutant human Na+ channels” Circ Res 79(1): 103-8, and Wang, D. W., K. Yazawa, et al. (1997) “Pharmacological targeting of long QT mutant sodium channels” J Clin Invest 99(7): 1714-20); for neuroprotection (See, Taylor, C. P. and L. S. Narasimhan (1997) “Sodium channels and therapy of central nervous system diseases” Adv Pharmacol 39: 47-98) and as anesthetics (See, Strichartz, G. R., Z. Zhou, et al. (2002) “Therapeutic concentrations of local anaesthetics unveil the potential role of sodium channels in neuropathic pain.” Novartis Found Symp 241: 189-201).

Various animal models with clinical significance have been developed for the study of sodium channel modulators for numerous different pain indications. E.g., malignant chronic pain, see, Kohase, H., et al., Acta Anaesthesiol Scand. 2004; 48(3):382-3; femur cancer pain (see, Kohase, H., et al., Acta Anaesthesiol Scand. 2004; 48(3):382-3); non-malignant chronic bone pain (see, Ciocon, J. O. et al, J Am Geriatr Soc. 1994; 42(6):593-6); rheumatoid arthritis (see, Calvino, B. et al., Behav Brain Res. 1987; 24(1):11-29); osteoarthritis (see, Guzman, R. E., et al., Toxicol Pathol. 2003; 31(6):619-24); spinal stenosis (see, Takenobu, Y. et al., J Neurosci Methods. 2001; 104(2):191-8); neuropathic low back pain (see, Hines, R., et al., Pain Med. 2002; 3(4):361-5; Massie, J. B., et al., J Neurosci Methods. 2004; 137(2):283-9); myofascial pain syndrome (see, Dalpiaz & Dodds, J Pain Palliat Care Pharmacother. 2002; 16(1):99-104; Sluka K A et al., Muscle Nerve. 2001; 24(1):37-46); fibromyalgia (see, Bennet & Tai, Int J Clin Pharmacol Res. 1995; 15(3):115-9); temporomandibular joint pain (see, Ime H, Ren K, Brain Res Mol Brain Res. 1999; 67(1):87-97); chronic visceral pain, including abdominal (see, Al-Chaer, E. D., et al., Gastroenterology. 2000; 119(5):1276-85); pelvic/perineal pain, (see, Wesselmann et al., Neurosci Lett. 1998; 246(2):73-6); pancreatic (see, Vera-Portocarrero, L. B., et al., Anesthesiology. 2003; 98(2):474-84); IBS pain (see, Verne, G. N., et al., Pain. 2003; 105(1-2):223-30; La J H et al., World Gastroenterol. 2003; 9(12):2791-5); chronic headache pain (see, Willimas & Stark, Cephalalgia. 2003; 23(10):963-71); migraine (see, Yamamura, H., et al., J. Neurophysiol. 1999; 81(2):479-93); tension headache, including cluster headaches (see, Costa, A., et al., Cephalalgia. 2000; 20(2):85-91); chronic neuropathic pain, including post-herpetic neuralgia (see, Attal, N., et al., Neurology. 2004; 62(2):218-25; Kim & Chung 1992, Pain 50:355); diabetic neuropathy (see, Beidoun A et al., Clin J. Pain. 2004; 20(3):174-8; Courteix, C., et al., Pain. 1993; 53(1):81-8); HIV-associated neuropathy (see, Portegies & Rosenberg, Ned Tijdschr Geneeskd. 2001; 145(15):731-5; Joseph E K et al., Pain. 2004; 107(1-2):147-58; Oh, S. B., et al., J Neurosci. 2001; 21(14):5027-35); trigeminal neuralgia (see, Sato, J., et al., Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004; 97(1):18-22; Imamura Y et al., Exp Brain Res. 1997; 116(1):97-103); Charcot-Marie Tooth neuropathy (see, Sereda, M., et al., Neuron. 1996; 16(5):1049-60); hereditary sensory neuropathies (see, Lee, M. J., et al., Hum Mol Genet. 2003; 12(15):1917-25); peripheral nerve injury (see, Attal, N., et al., Neurology. 2004; 62(2):218-25; Kim & Chung 1992, Pain 50:355; Bennett & Xie, 1988, Pain 33:87; Decostered, I. & Woolf, C. J., 2000, Pain 87:149; Shir, Y. & Seltzer, Z. 1990; Neurosci Lett 115:62); painful neuromas (see, Nahabedian & Johnson, Ann Plast Surg. 2001; 46(1):15-22; Devor & Raber, Behav Neural Biol. 1983; 37(2):276-83); ectopic proximal and distal discharges (see, Liu, X. et al., Brain Res. 2001; 900(1):119-27); radiculopathy (see, Devers & Galer, (see, Clin J. Pain. 2000; 16(3):205-8; Hayashi N et al., Spine. 1998; 23(8):877-85); chemotherapy induced neuropathic pain (see, Aley, K. O., et al., Neuroscience. 1996; 73(1):259-65); radiotherapy-induced neuropathic pain;

post-mastectomy pain (see, Devers & Galer, Clin J Pain. 2000; 16(3):205-8); central pain (Cahana, A., et al., Anesth Analg. 2004; 98(6):1581-4), spinal cord injury pain (see, Hains, B. C., et al., Exp Neurol. 2000; 164(2):426-37); post-stroke pain; thalamic pain (see, LaBuda, C. J., et al., Neurosci Lett. 2000; 290(1):79-83); complex regional pain syndrome (see, Wallace, M. S., et al., Anesthesiology. 2000; 92(1):75-83; Xantos D et al., J. Pain. 2004; 5(3 Suppl 2):S1); phanton pain (see, Weber, W. E., Ned Tijdschr Geneeskd. 2001; 145(17):813-7; Levitt & Heyback, Pain. 1981; 10(1):67-73); intractable pain (see, Yokoyama, M., et al., Can J Anaesth. 2002; 49(8):810-3); acute pain, acute post-operative pain (see, Koppert, W., et al., Anesth Analg. 2004; 98(4):1050-5; Brennan, T. J., et al., Pain. 1996; 64(3):493-501); acute musculoskeletal pain; joint pain (see, Gotoh, S., et al., Ann Rheum Dis. 1993; 52(11):817-22); mechanical low back pain (see, Kehl, L. J., et al., Pain. 2000; 85(3):333-43); neck pain; tendonitis; injury/exercise pain (see, Sesay, M., et al., Can J Anaesth. 2002; 49(2):137-43); acute visceral pain, including abdominal pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; etc (see, Giambernardino, M. A., et al., Pain. 1995; 61(3):459-69); chest pain, including cardiac Pain (see, Vergona, R. A., et al., Life Sci. 1984; 35(18):1877-84); pelvic pain, renal colic pain, acute obstetric pain, including labor pain (see, Segal, S., et al., Anesth Analg. 1998; 87(4):864-9); cesarean section pain; acute inflammatory, burn and trauma pain; acute intermittent pain, including endometriosis (see, Cason, A. M., et al., Horm Behav. 2003; 44(2):123-31); acute herpes zoster pain; sickle cell anemia; acute pancreatitis (see, Toma, H; Gastroenterology. 2000; 119(5):1373-81); breakthrough pain; orofacial pain, including sinusitis pain, dental pain (see, Nusstein, J., et al., J Endod. 1998; 24(7):487-91; Chidiac, J. J., et al., Eur J Pain. 2002; 6(1):55-67); multiple sclerosis (MS) pain (see, Sakurai & Kanazawa, J Neurol Sci. 1999; 162(2):162-8); pain in depression (see, Greene B, Curr Med Res Opin. 2003; 19(4):272-7); leprosy pain; behcet's disease pain; adiposis dolorosa (see, Devillers & Oranje, Clin Exp Dermatol. 1999; 24(3):240-1); phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain (see, Legroux-Crespel, E., et al., Ann Dermatol Venereol. 2003; 130(4):429-33); Fabry's disease pain (see, Germain, D. P., J Soc Biol. 2002; 196(2):183-90); Bladder and urogenital disease, including urinary incontinence (see, Berggren, T., et al., J Urol. 1993; 150(5 Pt 1):1540-3); hyperactivity bladder (see, Chuang, Y. C., et al., Urology. 2003; 61(3):664-70); painful bladder syndrome (see, Yoshimura, N., et al., J Neurosci. 2001; 21(21):8690-6); interstitial cyctitis (IC) (see, Giannakopoulos & Campilomatos, Arch Ital Urol Nefrol Androl. 1992; 64(4):337-9; Boucher, M., et al., J Urol. 2000; 164(1):203-8); and prostatitis (see, Mayersak, J. S., hit Surg. 1998; 83(4):347-9; Keith, I. M., et al., J Urol. 2001; 166(1):323-8).

Voltage-gated calcium channels are membrane-spanning, multi-subunit proteins that open in response to membrane depolarization, allowing Ca entry from the extracellular milieu. Calcium channels were initially classified based on the time and voltage-dependence of channel opening and on the sensitivity to pharmacological block. The categories were low-voltage activated (primarily T-type) and high-voltage activated (L,N,P,Q or R-type). This classification scheme was replaced by a nomenclature based upon the molecular subunit composition, as summarized in Table B (Hockerman G H, Peterson B Z, Johnson B D, Catterall W A. 1997. Annu Rev Pharmacol Toxicol 37: 361-96; Striessnig J. 1999. Cell Physiol Biochem 9: 242-69). There are four primary subunit types that make up calcium channels—α₁, α₂δ, β and

See, e.g., De Waard et al. Structural and functional diversity of voltage-activated calcium channels. In Ion Channels, (ed. T. Narahashi) 41-87, (Plenum Press, New York, 1996)). The α₁ subunit is the primary determinant of the pharmacological properties and contains the channel pore and voltage sensor (Hockerman et al., 1997; Striessnig, 1999). Ten isoforms of the α₁ subunit are known, as indicated in Table I below. The α₂δ subunit consists of two disulfide linked subunits, α₂, which is primarily extracellular, and a transmembrane δ subunit. Four isoforms of α₂δ are known, α₂δ-1, α₂δ-2, α₂δ-3 and α₂δ-4. The β subunit is a non-glycosylated cytoplasmic protein that binds to the α₁ subunit. Four isoforms are known, termed β₁ to β₄. The γsubunit is a transmembrane protein that has been biochemically isolated as a component of C_(v)1 and Ca_(v)2 channels. At least 8 isoforms are known (γ₁ to γ₈) [Kang M G, Campbell K P. 2003. J Biol Chem 278: 21315-8]. The nomenclature for voltage-gated calcium channels is based upon the content of the α₁ subunit, as indicated in Table B. Each type of α₁ subunit can associate with a variety of β, α₂δ or γ subunits, so that each Ca_(v) type corresponds to many different combinations of subunits.

TABLE B Cav Nomenclature α₁ subunit Pharmacological name Ca_(v)1.1 α_(1S) L-type Ca_(v)1.2 α_(1C) L-type Ca_(v)1.3 α_(1D) L-type Ca_(v)1.4 α_(1F) Ca_(v)2.1 α_(1A) P- or Q-type Ca_(v)2.2 α_(1B) N-type Ca_(v)2.3 α_(1E) R-type Ca_(v)3.1 α_(1G) T-type Ca_(v)3.2 α_(1H) T-type Ca_(v)3.3 α_(1I) T-type

Ca_(v)2 currents are found almost exclusively in the central and peripheral nervous system and in neuroendocrine cells and constitute the predominant forms of presynaptic voltage-gated calcium current. Presynaptic action potentials cause channel opening, and neurotransmitter release is steeply dependent upon the subsequent calcium entry. Thus, Ca_(v)2 channels play a central role in mediating neurotransmitter release.

Ca_(v)2.1 and Ca_(v)2.2 contain high affinity binding sites for the peptide toxins ω-conotoxin-MVIIC and ω-conotoxin-GVIA, respectively, and these peptides have been used to determine the distribution and function of each channel type. Ca_(v)2.2 is highly expressed at the presynaptic nerve terminals of neurons from the dorsal root ganglion and neurons of lamina I and II of the dorsal horn (Westenbroek R E, Hoskins L, Catterall W A. 1998. J Neurosci 18: 6319-30; Cizkova D, Marsala J, Lukacova N, Marsala M, Jergova S, et al. 2002. Exp Brain Res 147: 456-63). Ca_(v)2.2 channels are also found in presynaptic terminals between second and third order interneurons in the spinal cord. Both sites of neurotransmission are very important in relaying pain information to the brain.

Pain can be roughly divided into three different types: acute, inflammatory, and neuropathic. Acute pain serves an important protective function in keeping the organism safe from stimuli that may produce tissue damage. Severe thermal, mechanical, or chemical inputs have the potential to cause severe damage to the organism if unheeded. Acute pain serves to quickly remove the individual from the damaging environment. Acute pain by its very nature generally is short lasting and intense. Inflammatory pain, on the other hand, may last for much longer periods of time and its intensity is more graded. Inflammation may occur for many reasons including tissue damage, autoimmune response, and pathogen invasion. Inflammatory pain is mediated by an “inflammatory soup” that consists of substance P, histamines, acid, prostaglandin, bradykinin, CGRP, cytokines, ATP, and neurotransmitter release. The third class of pain is neuropathic and involves nerve damage that results in reorganization of neuronal proteins and circuits yielding a pathologic “sensitized” state that can produce chronic pain lasting for years. This type of pain provides no adaptive benefit and is particularly difficult to treat with existing therapies.

Pain, particularly neuropathic and intractable pain is a large unmet medical need. Millions of individuals suffer from severe pain that is not well controlled by current therapeutics. The current drugs used to treat pain include NSAIDS, COX2 inhibitors, opioids, tricyclic antidepressants, and anticonvulsants. Neuropathic pain has been particularly difficult to treat as it does not respond well to opioids until high doses are reached. Gabapentin is currently the favored therapeutic for the treatment of neuropathic pain although it works in only 60% of patients where it shows modest efficacy. The drug is however very safe and side effects are generally tolerable although sedation is an issue at higher doses.

Validation of Cav2.2 as a target for the treatment of neuropathic pain is provided by studies with ziconotide (also known as ω-conotoxin-MVIIA), a selective peptide blocker of this channel (Bowersox S S, Gadbois T, Singh T, Pettus M, Wang Y X, Luther R R. 1996. J Pharmacol Exp Ther 279: 1243-9; Jain K K. 2000. Exp. Opin. Invest. Drugs 9: 2403-10; Vanegas H, Schaible H. 2000. Pain 85: 9-18). In man, intrathecal infusion of Ziconotide is effective for the treatment of intractable pain, cancer pain, opioid resistant pain, and neuropathic pain. The toxin has an 85% success rate for the treatment of pain in humans with a greater potency than morphine. An orally available antagonist of Ca_(v)2.2 should have similar efficacy without the need for intrathecal infusion. Ca_(v)2.1 and Ca_(v)2.3 are also in neurons of nociceptive pathways and antagonists of these channels could be used to treat pain.

Antagonists of Ca_(v)2.1, Ca_(v)2.2 or Ca_(v)2.3 should also be useful for treating other pathologies of the central nervous system that apparently involve excessive calcium entry. Cerebral ischaemia and stroke are associated with excessive calcium entry due to depolarization of neurons. The Ca_(v)2.2 antagonist ziconotide is effective in reducing infarct size in a focal ischemia model using laboratory animals, suggesting that Ca_(v)2.2 antagonists could be used for the treatment of stroke. Likewise, reducing excessive calcium influx into neurons may be useful for the treatment of epilepsy, traumatic brain injury, Alzheimer's disease, multi-infarct dementia and other classes of dementia, amyotrophic lateral sclerosis, amnesia, or neuronal damage caused by poison or other toxic substances.

Ca_(v)2.2 also mediates release of neurotransmitters from neurons of the sympathetic nervous system and antagonists could be used to treat cardiovascular diseases such as hypertension, cardiac arrhythmia, angina pectoris, myocardial infarction, and congestive heart failure.

Unfortunately, as described above, the efficacy of currently used sodium channel blockers and calcium channel blockers for the disease states described above has been to a large extent limited by a number of side effects. These side effects include various CNS disturbances such as blurred vision, dizziness, nausea, and sedation as well more potentially life threatening cardiac arrhythmias and cardiac failure. Accordingly, there remains a need to develop additional Na channel and Ca channel antagonists, preferably those with higher potency and fewer side effects. Unfortunately, as described above, the efficacy of currently used sodium channel blockers and calcium channel blockers for the disease states described above has been to a large extent limited by a number of side effects. These side effects include various CNS disturbances such as blurred vision, dizziness, nausea, and sedation as well more potentially life threatening cardiac arrhythmias and cardiac failure. Accordingly, there remains a need to develop additional Na channel and Ca channel antagonists, preferably those with higher potency and fewer side effects.

SUMMARY OF THE INVENTION

In general, the invention relates to compounds useful as ion channel modulators. It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are useful as inhibitors of voltage-gated sodium channels. These compounds have the general formula I:

or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, R₃, R₄, X, Y and n are described generally below.

In another aspect, compounds of this invention, and pharmaceutically acceptable compositions thereof, are useful as inhibitors of voltage-gated sodium channels and/or calcium channels. These compounds have the general formula Ia:

or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, R₃, R₄, X, and n are described generally below.

The present invention also includes methods for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of calcium and/or sodium ion channels is implicated in the disease state. Methods for treating or lessening the severity of a pain condition are also disclosed. In one aspect, the method comprises the step of administering to the patient an effective amount of a pharmaceutical composition comprising at least one compound of the present invention.

The compounds of the present invention are useful for treating or lessening the severity of diseases, disorders, or conditions, including, but not limited to, acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, or cancer pain.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

The term “modulating” as used herein means increasing or decreasing, e.g. activity, by a measurable amount. Compounds that modulate ion channel activity, such as calcium ion channel activity and/or sodium ion channel activity, by increasing the activity of the ion channel, e.g., a calcium ion channel and/or a sodium ion channel, are called agonists. Compounds that modulate ion channel activity, such as calcium ion channel activity and/or sodium ion channel activity, by decreasing the activity of the ion channel, e.g., calcium ion channel and/or sodium ion channel, are called antagonists. An agonist interacts with an ion channel, such as calcium ion channel, to increase the ability of the receptor to transduce an intracellular signal in response to endogenous ligand binding. An antagonist interacts with an ion channel and competes with the endogenous ligand(s) or substrate(s) for binding site(s) on the receptor to decrease the ability of the receptor to transduce an intracellular signal in response to endogenous ligand binding.

The phrase “treating or reducing the severity of an ion channel mediated disease” refers both to treatments for diseases that are directly caused by ion channel activities and alleviation of symptoms of diseases not directly caused by ion channel activities. Examples of diseases whose symptoms may be affected by ion channel activities include, but are not limited to, acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, or cancer pain.

As described herein, compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.

As used herein the term “aliphatic’ encompasses the terms alkyl, alkenyl, alkynyl.

As used herein, an “alkyl” group refers to a saturated aliphatic hydrocarbon group containing 1-8 (e.g., 1-6 or 1-4) carbon atoms. An alkyl group can be straight or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyl. An alkyl group can be optionally substituted with one or more substituents such as halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, alkoxycarbonyl, alkoxycarbonylamino, alkylcarbonyloxy, nitro, cyano, amino, acyl, sulfonyl, sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carbamoyl, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, or hydroxyl.

As used herein, an “alkenyl” group refers to an aliphatic carbon group that contains 2-10 (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) carbon atoms and at least one double bond. Like an alkyl group, an alkenyl group can be straight or branched. Examples of an alkenyl group include, but are not limited to, allyl, isoprenyl, 2-butenyl, and 2-hexenyl. An alkenyl group may be optionally substituted with one or more substituents such as halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, alkoxycarbonyl, alkylcarbonyloxy, nitro, cyano, amino, acyl, sulfonyl, sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carbamoyl, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, or hydroxyl.

As used herein, an “alkynyl” group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and at least one triple bond. Like an alkyl group, an alkynyl group can be straight or branched. An alkynyl group may be optionally substituted with one or more substituents such as halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, alkoxycarbonyl, alkylcarbonyloxy, nitro, cyano, amino, acyl, sulfonyl, sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carbamoyl, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, or hydroxyl.

As used herein, an “amino” group refers to —NR^(X)R^(Y) wherein each of R^(X) and R^(Y) is independently hydrogen, alkyl, cycloalkyl, sulfonyl, (cycloalkyl)alkyl, aryl, aralkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, or heteroaralkyl each of which are defined herein and are optionally substituted. When the term “amino” is not the terminal group (e.g., alkylcarbonylamino), it is represented by —NR^(X)—. R^(X) has the same meaning as defined above.

As used herein, an “aryl” group used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl” refers to monocyclic (e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl); tricyclic (e.g., fluorenyl, tetrahydrofluorenyl, anthracenyl, or tetrahydroanthracenyl); or a benzofused group having 3 rings. For example, a benzofused group includes phenyl fused with two or more C₄₋₈ carbocyclic moieties. An aryl is optionally substituted with one or more substituents including aliphatic (e.g., alkyl, alkenyl, or alkynyl); cycloalkyl; (cycloalkyl)alkyl; heterocycloalkyl; (heterocycloalkyl)alkyl; aryl; heteroaryl; alkoxy; cycloalkyloxy; heterocycloalkyloxy; aryloxy; heteroaryloxy; aralkyloxy; heteroaralkyloxy; aroyl; heteroaroyl; amino; aminoalkyl; nitro; —C(O)OH; carbonyl (e.g., alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, (alkylamino)alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl; or sulfonylcarbonyl); aralkylcarbonyloxy; sulfonyl (e.g., alkylsulfonyl or aminosulfonyl); sulfinyl (e.g., allylsulfinyl); sulfanyl alkylsulfanyl); cyano; halo; hydroxyl; acyl; mercapto; sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl. Alternatively, an aryl may be unsubstituted.

Examples of substituted aryls include haloaryl, alkoxycarbonylaryl, alkylaminoalkylaminocarbonylaryl, p,m-dihaloaryl, p-amino-p-alkoxycarbonylaryl, m-amino-m-cyanoaryl, aminoaryl, alkylcarbonylaminoaryl, cyanoalkylaryl, alkoxyaryl, aminosulfonylaryl, alkylsulfonylaryl, aminoaryl, p-halo-m-aminoaryl, cyanoaryl, hydroxyalkylaryl, alkoxyalkylaryl, hydroxyaryl, carboxyalkylaryl, dialkylaminoalkylaryl, m-heterocycloaliphatic-o-alkylaryl, heteroarylaminocarbonylaryl, nitroalkylaryl, alkylsulfonylaminoalkylaryl, heterocycloaliphaticcarbonylaryl, alkylsulfonylalkylaryl, cyanoalkylaryl, heterocycloaliphaticcarbonylaryl, alkylcarbonylaminoaryl, hydroxyalkylaryl, alkylcarbonylaryl, aminocarbonylaryl, alkylsulfonylaminoaryl, dialkylaminoaryl, alkylaryl, and trihaloalkylaryl.

As used herein, an “araliphatic” group refers to an aliphatic group (e.g., a C₁₋₄ alkyl group, a C₁₋₄ alkenyl group, or a C₁₋₄ alkynyl group) that is substituted with an aryl group. Both “aliphatic” and “aryl” have been defined above.

As used herein, an “aralkyl” group refers to an alkyl group (e.g., a C₁₋₄ alkyl group) that is substituted with an aryl group. Both “alkyl” and “aryl” are defined herein. An example of an aralkyl group is benzyl.

As used herein, a “bicyclic ring system” includes 7-12 (e.g., 9, 10, or 11) membered structures that form two rings, wherein the two rings have at least one atom in common (e.g., 2 atoms in common). Bicyclic ring structures include bicycloaliphatics (e.g., bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatics (e.g., bicycloheteroalkyl or bicycloheteroalkenyl), bicyclic aryls, and bicyclic heteroaryls.

The term “cycloaliphatic” means a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic hydrocarbon ring that has a single point of attachment to the rest of the molecule. Cycloaliphatic rings are 3-8 membered monocyclic rings (e.g., 3-6 membered rings). Cycloaliphatic rings also include 8-12 membered bicyclic hydrocarbon rings, (e.g., 10 membered bicyclic hydrocarbon rings). A cycloaliphatic group encompasses a “cycloalkyl” group and a “cycloalkenyl” group.

As used herein, a “cycloalkyl” group refers to a saturated carbocyclic mono-, bi-, or tri-, or multicyclic (fused or bridged) ring of 3-10 (e.g., 5-10) carbon atoms. Without limitation, examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or the like. Without limitation, examples of bicyclic cycloalkyl groups include octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, or the like. Without limitation, multicyclic groups include adamantyl, cubyl, norbornyl, or the like. Cycloalkyl rings can be optionally substituted at any chemically viable ring position.

A “cycloalkenyl” group, as used herein, refers to a non-aromatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or more double bonds. Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl, bicyclo[2.2.2]octenyl, and bicyclo[3.3.1]nonenyl. Cycloalkenyl ring structures can be optionally substituted at any chemically viable position on the ring or rings.

A cycloalkyl or cycloalkenyl group can be optionally substituted with one or more substituents such as aliphatic (e.g., alkyl, alkenyl, or alkynyl), cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl)alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxyl, acyl, mercapto, sulfonyl (e.g., alkylsulfonyl or arylsulfonyl), sulfinyl (e.g., alkylsulfinyl), sulfanyl (e.g., alkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carbamoyl, or the like.

Without limitation, examples of substituted cycloaliphatics include alkylcycloalkyl (e.g., propylcyclohexyl), alkylbicyclo[3.1.1]heptyl, alkylcycloalkenyl, or the like.

As used herein, the term “heterocycloaliphatic” and “heterocyclic” encompasses a heterocycloalkyl group and a heterocycloalkenyl group.

As used herein, a “heterocycloalkyl” group refers to a 3-10 membered mono or bicyclic (fused or bridged) (e.g., 5 to 10 membered mono or bicyclic) saturated ring structure, in which one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof). Examples of a heterocycloalkyl group include optionally substituted piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,4-dioxolanyl, 1,4-dithianyl; 1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholinyl, octahydro-benzofuranyl, octahydro-chromenyl, octahydro-thiochromenyl, octahydro-indolyl, octahydro-pyrindinyl, decahydro-quinolinyl, octahydro-benzo[b]thiophenyl, 2-oxa-bicyclo[2.2.2]octyl, 1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octanyl, 2,6-dioxa-tricyclo[3.3.1.0^(3,7)]nonyl, tropane. A monocyclic heterocycloalkyl group may be fused with a phenyl moiety such as tetrahydroisoquinoline. Heterocycloalkyl ring structures can be optionally substituted at any chemically viable position on the ring or rings.

A “heterocycloalkenyl” group, as used herein, refers to a mono- or bicyclic (e.g., 5- to 10-membered mono- or bicyclic) non-aromatic ring structure having one or more double bonds, and wherein one or more of the ring atoms is a heteroatom (e.g., N, O, or S). Examples of heterocycloalkenyls include 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, or 2-pyrazolyl. Monocyclic heterocycloaliphatics are numbered according to standard chemical nomenclature. For instance:

Heterocycloalkenyl ring structures can be optionally substituted at any chemically viable position on the ring or rings.

A heterocycloalkyl or heterocycloalkenyl group can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl (such as a benzimidazolidinyl), (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy (two alkoxy groups on the same atom or adjacent atoms may form a ring together with the atom(s) to which they are bound), cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl)alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxyl, acyl, mercapto, sulfonyl (such as alkylsulfonyl or arylsulfonyl), sulfinyl (such as alkylsulfinyl), sulfanyl (such as alkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

Without limitation, examples of substituted heterocycloaliphatics include alkoxycarbonylheterocycloalkyl (e.g., ethoxycarbonyltropane), alkoxycarbonylheterocycloalkyl (e.g., ethoxycarbonylpiperidyl), or the like.

A “heteroaryl” group, as used herein, refers to a monocyclic, bicyclic, or tricyclic ring structure having 4 to 15 ring atoms wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof) and wherein one or more rings of the bicyclic or tricyclic ring structure is aromatic. A heteroaryl group includes a benzofused ring system having 2 to 3 rings. For example, a benzofused group includes benzo fused with one or two C₄₋₈ heterocyclic moieties (e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, quinolinyl, or isoquinolinyl). Some examples of heteroaryl are azetidinyl, pyridinyl, 1H-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[1,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo-1,2,5-thiadiazolyl, or 1,8-naphthyridyl.

Without limitation, monocyclic heteroaryls include furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4-H-pyranyl, pyridinyl, pyridazinyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl. Monocyclic heteroaryls are numbered according to standard chemical nomenclature. For instance:

Without limitation, bicyclic heteroaryls include indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, quinolinyl, isoquinolinyl, indolizyl, isoindolyl, indazolyl, benzimidazyl, benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, or pteridyl. Bicyclic heteroaryls are numbered according to standard chemical nomenclature. For instance:

A heteroaryl is optionally substituted with one or more substituents such as aliphatic including alkyls (e.g., alkoxyalkyl, carboxyalkyl, hydroxyallyl, oxoalkyl, aralkyl, (alkylsulfonylamino)alkyl, (sulfonylamino)alkyl, cyanoalkyl, aminoallyl, oxoalkyl, alkoxycarbonylalkyl, (cycloalkyl)alkyl heterocycloalkyl, (heterocycloalkyl)alkyl aralkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl; cycloaliphatic including cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl); heterocycloaliphatic including heterocycloalkyl (e.g., thiomorpholinyl, piperazinyl, 1,3,5-trithianyl, morpholinyl, pyrrolyl, 1,3-dioxolanyl, pyrazolidyl, or piperidinyl); aryl, heteroaryl (e.g., quinolyl, indolyl, 3H-indolyl, isoindolyl, benzo[b]-4H-pyranyl, cinnolyl, quinoxylyl, benzimidazyl, benzo-1,2,5-thiadiazolyl, benzo-1,2,5-oxadiazolyl, or benzthiophenyl); alkoxy; cycloalkyloxy; heterocycloalkyloxy; aryloxy; heteroaryloxy; aralkyloxy; heteroaralkyloxy; aroyl; heteroaroyl; amino (e.g., carbonylamino, alkylcarbonylamino, alkylsulfonylamino, arylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, (heterocycloalkyl)carbonylamino, (cycloalkyl)alkylcarbonylamino, sulfanylamino, and (heterocycloalkyl)alkylcarbonylamino); nitro; carboxy; carbonyl (e.g., alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, arylaminocarbonyl, thiazoleaminocarbonyl, thiomorpholinecarbonyl, aminoalkylaminocarbonyl); alkylcarbonyloxy; cyano; halo; hydroxyl; acyl; mercapto; sulfonyl (e.g., aminosulfonyl, allylsulfonyl, morpholinesulfonyl, or arylsulfonyl); sulfinyl (e.g., alkylsulfinyl); sulfanyl (e.g., alkylsulfanyl); sulfoxy; urea; thiourea; sulfamoyl; sulfamide; oxo; or carbamoyl.

A “heteroaraliphatic” group, as used herein, refers to an aliphatic group (e.g., C₁₋₄ alkyl group, C₁₋₄ alkenyl group, or C₁₋₄ alkynyl group) that is substituted with a heteroaryl group. Both “aliphatic” and “heteroaryl” have been defined above.

A “heteroaralkyl” group, as used herein, refers to an alkyl group (e.g., a C₁₋₄ alkyl group) that is substituted with a heteroaryl group. Both “alkyl” and “heteroaryl” have been defined above.

As used herein, “cyclic moiety” includes cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl, each of which has been defined previously.

As used herein, “cyclic group” includes mono-, bi-, and tri-cyclic structures including cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, each of which has been previously defined.

As used herein, an “acyl” group refers to a formyl group or alkyl-C(═O)— (also referred to as “alkylcarbonyl”) where “alkyl” has been defined previously. Acetyl and pivaloyl are examples of acyl groups.

As used herein, a “carbonyl” group, when used alone or as part of another structure refers to the structure —C(O)—.

As used herein, a “carbamoyl” group refers to a group having the structure —O—CO—NR^(X)R^(Y) or —NR^(X)—CO—O—R^(Z) wherein R^(X) and R^(Y) have been defined above and R^(Z) can be alkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl.

As used herein, a “carboxy” and a “sulfo” group refer to —C(O)OH or —C(O)OR^(X) and —SO₃H or —SO₃R^(X), respectively.

As used herein, an “alkoxy” group refers to an alkyl-O— group where “alkyl” has been defined previously. Moreover an alkoxy group includes structures comprising two alkoxy groups on the same atom or adjacent atoms that form a ring together with the atom(s) to which they are bound.

As used herein, a “sulfoxy” group refers to —O—SO—R^(X) or —SO—O—R^(X), where R^(X) has been defined above.

As used herein, a “mercapto” group refers to —SH.

As used herein, a “sulfonyl” group refers to —S(O)₂—.

As used herein a “sulfinyl” group refers to —S(O)—.

As used herein a “sulfanyl” group refers to —S—.

As used herein, a “halogen” or “halo” group refers to fluorine, chlorine, bromine or iodine.

As used herein, a “haloaliphatic” group refers to an aliphatic group substituted with 1-3 halogen. For instance, the term haloalkyl includes the group —CF₃.

As used herein, a “sulfamoyl” group refers to the structure —S(O)₂—NR^(X)R^(Y) or —NR^(X)—S(O)₂—R^(Z) wherein R^(X), R^(Y), and R^(Z) have been defined above.

As used herein, a “sulfamide” group refers to the structure —NR^(X)—S(O)₂—NR^(Y)R^(Z) wherein R^(X), R^(Y), and R^(Z) have been defined above.

As used herein, a “carbonylamino” group used alone or in connection with another group refers to an amido group such as R^(X)—C(O)—NR^(X)—. For instance an alkylcarbonylamino includes alkyl-C(O)—NR^(X)—, wherein R^(X) has been defined above.

As used herein, a “aminocarbonyl” group used alone or in connection with another group refers to an amido group such as N(R^(X))₂—C(O)—.

As used herein, an “alkoxycarbonyl” used alone or in connection with another group refers to a carbonyl group such as alkyl-O—C(O)—.

As used herein, an “alkoxyalkyl” refers to an alkyl group such as alkyl-O-alkyl-, wherein alkyl has been defined above.

As used herein, an “aminocarbonyl” refers to an amido group such as —NR^(X)—C(O)—, wherein R^(X) has been defined above.

As used herein, an “aminosulfonyl” refers to the structure —N(R^(X))₂—S(O)₂—, wherein R^(X) has been defined above.

As used herein, an “oxo” refers to ═O.

As used herein, an “aminoalkyl” refers to the structure N(R^(X))₂-alkyl-.

As used herein, a “cyanoalkyl” refers to the structure (CN)-alkyl-.

As used herein, an “alkylsulfonyl’ group refers to the structure alkyl-S(O)₂—.

As used herein, a “sulfonylamino” group refers to the structure R^(X)—S(O)₂—N(R^(X))₂—, wherein R^(X) has been defined above.

As used herein, a “guanidinyl” group refers to the structure NH₂C(NH)NH—.

As used herein, an “aliphatic chain” refers to a branched or straight aliphatic group. A straight aliphatic chain has the structure —[CH₂]_(p)—, where p is 1-6. A branched aliphatic chain is a straight aliphatic chain that is substituted with one or more aliphatic groups. A branched aliphatic chain has the structure —[CHW]_(p)— where W is hydrogen or an aliphatic group; however, W shall be an aliphatic group in at least one instance.

As used herein, a “urea” group refers to the structure —NR^(X)—CO—NR^(Y)R^(Z) and a “thiourea” group refers to the structure —NR^(X)—CS—NR^(Y)R^(Z). R^(X), R^(Y), and R^(Z) have been defined above.

In general, the term “substituted,” whether preceded by the term “optionally” or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described above in the definitions and below in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. A ring substituent, such as a heterocycloalkyl, may be bound to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings share one common atom. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.

The phrase “stable or chemically feasible,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40° C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

As used herein, an effective amount is defined as the amount required to confer a therapeutic effect on the treated patient, and is typically determined based on age, surface area, weight, and condition of the patient. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al., Cancer Chemother. Rep., 50: 219 (1966). Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 537 (1970). As used herein, “patient” refers to a mammal, including a human.

As used herein, “patient” refers to a mammal, including a human.

Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

II. Compounds A. Generic Compounds

The present invention provides a method of modulating a sodium ion channel comprising the step of contacting said ion channel with a compound of formula I:

or a pharmaceutically acceptable salt thereof.

Each X is defined by —Z^(A)R₆, wherein each Z^(A) is independently a bond or an optionally substituted branched or straight C₁₋₆ aliphatic chain wherein up to two carbon units of Z^(A) are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR^(A)—, —CONR^(A)NR^(A)—, —CO₂—, —OCO—, —NR^(A)CO₂—, —O—, —NR^(A)CONR^(A)—, —OCONR^(A)—, —NR^(A)NR^(A), NR^(A)NR^(A)CO—, —NR^(A)CO—, —S—, —SO—, —SO₂—, —NR^(A)—, —SO₂NR^(A)—, —NR^(A)SO₂—, or —NR^(A)SO₂NR^(A)—.

Each R₄ is independently R^(A), halo, —OH, —NH₂, —NO₂, —CN, —CF₃, or —OCF₃.

Each R^(A) is independently hydrogen, an optionally substituted C₁₋₈ aliphatic group; a 3-8 membered optionally substituted fully saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an 8-12 membered optionally substituted fully saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R^(A) are taken together with the atom(s) to which they are attached to form an optionally substituted 3-12 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Each n is 1-4.

Each R₁ and R₂ is defined by —Z^(B)R₇, wherein each Z^(B) is independently a bond or an optionally substituted straight or branched C₁₋₆ aliphatic chain wherein up to two carbon units of Z^(B) are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR^(B)—, —CONR^(B)NR^(B)—, —CO₂—, —OCO—, —NR^(B)CO₂—, —O—, —NR^(B)CONR^(B)—, —OCONR^(B)—, —NR^(B)NR^(B), —NR^(B)NR^(B)CO—, —NR^(B)CO—, —S—, —SO—, —SO₂—, —NR^(B)—, —SO₂NR^(B)—, —NR^(B)SO₂—, or —NR^(B)SO₂NR^(B)—.

Each R⁷ is independently R^(B), halo, —OH, —NHC(NH)NH₂, —NH₂, —NO₂, —CN, —CF₃, or —OCF₃.

Each R^(B) is independently hydrogen, an optionally substituted C₁₄ aliphatic group, an optionally substituted 3-8 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an optionally substituted 8-12 membered fully saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R^(B) are taken together with the atom(s) to which they are attached to form an optionally substituted 3-12 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Each R₃ and R₄ is defined by —Z^(C)R₈, wherein each Z^(C) is independently a bond or an optionally substituted straight or branched C₁₋₆ aliphatic chain wherein up to two carbon units of Z^(C) are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR^(C)—, —CONR^(C)NR^(C)—, —CO₂—, —OCO—, —NR^(C)CO₂—, —O—, —NR^(C)CONR^(C)—, —OCONR^(C)—, —NR^(C)NR^(C), —NR^(C)NR^(C)CO—, —NR^(C)CO—, —S—, —SO—, —SO₂—, —NR^(C)—, —SO₂NR^(C)—, —NR^(C)SO₂—, or —NR^(C)SO₂NR^(C)—.

Each R₈ is independently R^(C), halo, —OH, —NH₂, —NO₂, —CN, —CF₃, or —OCF₃.

Each R^(C) is independently hydrogen, or an optionally substituted C₁₋₃ aliphatic group, an optionally substituted 3-8 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an optionally substituted 8-12 membered fully saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R^(C) are taken together with the atom(s) to which they are attached to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Each Y is hydrogen or unsubstituted C₁₋₃ alkyl.

B. Specific Embodiments

1. Substituents R₁ and R₂

Each R₁ and R₂ are defined by —Z^(B)R₇, wherein each Z^(B) is independently a bond, or an optionally substituted straight or branched C₁ aliphatic chain wherein up to two carbon units of Z^(B) are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR^(B)—, —CONR^(B)NR^(B)—, —CO₂—, —OCO—, —NR^(B)CO₂—, —O—, —NR^(B)CONR^(B)—, —OCONR^(B)—, —NR^(B)NR^(B), —NR^(B)NR^(B)CO—, —NR^(B)CO—, —S—, —SO—, —SO₂—, —NR^(B)—, —SO₂NR^(B)—, —NR^(B)SO₂—, or —NR^(B)SO₂NR^(B)—.

Each R⁷ is independently R^(B), halo, —OH, —NHC(NH)NH₂, —NH₂, —NO₂, —CN, —CF₃, or —OCF₃.

Each R^(B) is independently hydrogen, an optionally substituted C₁₋₈ aliphatic group, an optionally substituted 3-8 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an optionally substituted 8-12 membered fully saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R^(B) are taken together with the atom(s) to which they are attached to form an optionally substituted 3-12 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each of which is optionally substituted with 1 to 3 substituents.

In several embodiments, R₁ and R₂ are independently hydrogen; or C₁₋₈ aliphatic, araliphatic, heteroaralkyl, alkoxyalkyl, heterocycloaliphatic, guanidinylalkyl, aryloxyalkyl, C₁₋₆ cycloaliphatic; or R₁ and R₂ together with the nitrogen atom to which they are attached form an optionally substituted 5-8 membered fully saturated, partially unsaturated, or fully unsaturated heterocyclic ring.

In several other embodiments, one of R₁ and R₂ is an optionally substituted araliphatic or arylcycloaliphatic. Several examples of R₁ or R₂ include —C₁₋₃ aliphatic-aryl that is optionally substituted. In another set of examples, R₁ or R₂ is optionally substituted arylcycloalkyl (e.g., -cyclopropyl-aryl, -cyclobutyl-aryl, -cyclopentyl-aryl, or the like). In still other examples, R₁ or R₂ is optionally substituted monocyclic or bicyclic aralkyl. Several more examples of R₁ or R₂ include optionally substituted —C₁₋₃ aliphatic-phenyl (e.g., phenylmethyl, phenylethyl, phenylpropyl). In other examples, R₁ or R₂ is optionally substituted bicyclic —C₁₋₃ aliphatic-aryl (e.g., —C₁₋₃ aliphatic-naphthyl or —C₁₋₃ aliphatic-indenyl). In other examples, R₁ or R₂ is a naphthylmethyl, naphthylethyl, naphthylpropyl, indenylmethyl, indenylethyl, or indenylpropyl, each of which is optionally substituted. In other examples, R₁ or R₂ is an unsubstituted naphthylmethyl, naphthylethyl, naphthylpropyl, indenylmethyl, indenylethyl, or indenylpropyl. In several embodiments, R₁ or R₂ is a substituted aralkyl or arylcycloalkyl. For example, R₁ or R₂ is an aralkyl that is substituted at any chemically feasible position along the aliphatic chain, or on the aryl group. In several embodiments, R₁ or R₂ is substituted with 1-3 of halo, hydroxy, cyano, nitro, aliphatic, haloaliphatic, alkylamino, cycloaliphatic, heterocycloaliphatic, (heterocycloaliphatic)alkyl, aminocarbonyl, aryl, heteroaryl, or combinations thereof, each of which is optionally substituted. In one embodiment, R₁ or R₂ is an unsubstituted aralkyl. In one example, R₁ or R₂ is an unsubstituted phenylmethyl, unsubstituted phenylethyl, or an unsubstituted phenylpropyl.

In several other embodiments, R₁ or R₂ is a C₁₋₈ aliphatic that is optionally substituted with 1-3 substituents. In several embodiments, R₁ or R₂ are optionally substituted straight (e.g., ethyl, propyl, sec-butyl, or the like) or branched (e.g., isopropyl, isobutyl, sec-propyl, sec-butyl, or the like) aliphatic. For example, R₁ or R₂ is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl, each substituted with 1-3 substituents (e.g., 1-2 substituents). In other examples, R₁ or R₂ is an isopropyl that is optionally substituted with 1-2 substituents, or R₁ or R₂ is an unsubstituted isopropyl. In more examples, R₁ or R₂ is a sec-propyl that is substituted with 1-2 substituents. In several embodiments, R₁ or R₂ is substituted with 1-3 halo, cyano, hydroxy, or optionally substituted aryl, aryloxy, alkylamino, heteroaryl, cycloaliphatic, heterocycloaliphatic, or combinations thereof. In another embodiment, R₁ or R₂ is substituted with alkoxyalkyl. In other embodiments, R₁ or R₂ is unsubstituted methyl or sec-propyl.

In other embodiments, R₁ or R₂ is an optionally substituted monocyclic or bicyclic cycloaliphatic. For example, R₁ or R₂ is an optionally substituted monocyclic C₃₋₄ cycloaliphatic. In other examples, R₁ or R₂ is fully saturated or partially unsaturated. In other examples, R₁ or R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, each of which is optionally substituted with 1-2 substituents. For, example, In some embodiments, R₁ or R₂ is unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In other embodiments, R₁ or R₂ is substituted cyclopropyl. For example, R₁ or R₂ is substituted with 1-3 of halo, hydroxy, aliphatic, aryl, heteroaryl, or combinations thereof. In other embodiments, R₁ or R₂ is an optionally substituted bicyclic cycloaliphatic. In other examples, R₁ or R₂ is an optionally substituted bridged bicyclic cycloaliphatic. In other embodiments, R₁ or R₂ is optionally substituted bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl, or bicyclo[2.2.1]heptyl. In more examples R₁ or R₂ is unsubstituted bicyclo[2.1.1]hexyl, or bicyclo[2.2.1]heptyl substituted with 1-3 methyl groups. In another example, R₁ or R₂ is 2,6,6-trimethylbicyclo[3.1.1]heptyl.

In some embodiments, R₁ or R₂ is an optionally substituted aryl. For example, R₁ or R₂ is an optionally substituted 6-10 membered monocyclic or bicyclic aryl. In other examples, R₁ or R₂ is an optionally substituted phenyl, indenyl, dihydroindenyl or naphthyl. In other embodiments, R₁ or R₂ is substituted with 1-2 halo, hydroxy, cyano, or optionally substituted aliphatic, alkoxy, aryl, or heteroaryl; or combinations thereof. In other embodiments, R₁ or R₂ is unsubstituted phenyl, indenyl, dihydroindenyl or naphthyl.

In some embodiments, R₁ or R₂ is an optionally substituted monocyclic or bicyclic heterocycloaliphatic including 1-3 heteroatoms selected from N, O, and S. In one group of examples, R₁ or R₂ is fully saturated or partially unsaturated. In one group of examples, R₁ or R₂ is an optionally substituted fully saturated monocyclic heterocycloaliphatic. In another group of examples, R₁ or R₂ is morpholinyl, pyrroldinyl, thiomorpholinyl, tetrahydro-2H-pyranyl, or tetrahydrothiophenyl, each of which is optionally substituted. For example, R₁ or R₂ is morpholinyl, pyrroldinyl, thiomorpholinyl, tetrahydro-2H-pyranyl, or tetrahydrothiophenyl, each of which is optionally substituted with 1-3 substituents selected from halo, hydroxyl, aliphatic, or aryl. In another group of examples, R₁ or R₂ is unsubstituted morpholinyl, thiomorpholinyl, tetrahydro-2H-pyranyl, or tetrahydrothiophenyl. In another group of examples, R₁ or R₂ is an unsubstituted tropane.

In some embodiments, R₁ or R₂ is an optionally substituted heteroaraliphatic. In some embodiments, R₁ or R₂ includes a straight or branched aliphatic chain. For example, R₁ or R₂ includes a straight C₁₋₄ aliphatic chain. In another example, R₁ or R₂ is optionally substituted —C₁₋₃ aliphatic-heteroaryl. As noted above, R₁ or R₂ can be substituted at any chemically feasible position on the aliphatic chain or on the heteroaryl group. In other embodiments, R₁ or R₂ includes a 6-10 membered monocyclic or bicyclic heteroaryl group attached to the core structure with a C₁₋₃ aliphatic chain. For example, R₁ or R₂ is an optionally substituted 2,3-dihydrobenzofurylalkyl, indolinylalkyl, 2,3-dihydrobenzo[b][1,4]dioxinylalkyl, benzo[d][1,3]dioxolylalkyl, pyridinylalkyl, isoindolinylalkyl, or quinolinylalkyl. In other examples, R₁ or R₂ is an unsubstituted heteroaralkyl.

In some embodiments, R₁ or R₂ is an optionally substituted heteroaryl. For example, R₁ or R₂ is 2,3-dihydrobenzo[b][1,4]dioxinyl, or benzo[d][1,3]dioxolyl, each of which is optionally substituted. In several examples, R₁ or R₂ is unsubstituted 2,3-dihydrobenzo[b][1,4]dioxinyl, or benzo[d][1,3]dioxolyl.

In several other embodiments, R₁, R₂, and the nitrogen atom to which they are attached form an optionally substituted 4-12 membered monocyclic or bicyclic fully saturated or partially unsaturated ring having 1-3 heteroatoms. In several examples, R₁ and R₂ form a morpholinyl, piperadinyl, piperazinyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, imidazolidinyl, pyrazolyl, pyrazolidinyl, thiomorpholinyl, or 3,4-dihydro-benzo[b][1,4]oxazine, each of which is optionally substituted with 1-3 substituents independently selected from halo, alkylcarbonyl, C₁₋₄ alkyl, ethyl, alkoxy, and heterocycloalkyl. In another embodiment, R₁, R₂, and the nitrogen atom to which they are attached form a partially saturated heterocyclic ring that is optionally substituted with 1-2 substituents. For example, R₁, R₂, and the nitrogen atom to which they are attached form a substituted 1,2,3,6-tetrahydropyridinyl. In other examples, R₁, R₂, and the nitrogen atom to which they are attached form a piperidinyl, or tetrahydropyridinyl substituted with 1-2 substituents selected from alkyl, alkylcarbonyl, alkoxy, haloaryl, alkoxyaryl, or aryl. In other examples, R₁, R₂, and the nitrogen atom to which they are attached form an unsubstituted fully saturated or partially unsaturated heterocycloaliphatic.

In some embodiments, R₁ and R₂ together with the nitrogen atom to which they are attached form an optionally substituted 5-10 membered monocyclic or bicyclic ring that is partially unsaturated, or fully unsaturated, and has 1-3 heteroatoms selected from N, O, and S. In several embodiments, R₁ and R₂ together with the nitrogen atom to which they are attached form an optionally substituted monocyclic or bicyclic heteroaryl. In several examples, the heteroaryl formed from R₁, R₂, and the nitrogen atom to which they are attached is substituted with 1-3 of halo, cyano, hydroxyl, alkoxy, aliphatic, aryl, or cycloaliphatic. For example, R¹, R₂, and the nitrogen atom to which they are attached are optionally substituted indolinyl, 1,2,3,4-tetrahydroquinolinyl, or 3,4-dihydro-2H-benzo[b][1,4]oxazinyl. In other examples, the heteroaryl formed from R¹, R₂, and the nitrogen atom to which they are attached is substituted with 1-2 aliphatic groups. In other examples, the heteroaryl formed from R₁, R₂, and the nitrogen atom to which they are attached is substituted with 1-2 methyl groups.

In some embodiments, R₁ or R₂ is hydrogen.

In some embodiments, R₁ or R₂ is an optionally substituted guanidinylalkyl having 1-2 substituents. In other embodiments, R₁ or R₂ is an unsubstituted guanidinylalkyl.

In several embodiments, R₁ and R₂ are each independently selected from: hydrogen, methyl, ethyl,

In several embodiments, R₁, R₂ and the nitrogen atom to which they are attached form a heterocycloaliphatic or a heterocycloaliphatic fused with phenyl selected from:

2. Substituents R₃ and R₄

Each R₃ and R₄ are defined by —Z^(C)R₈, wherein each Z^(C) is independently a bond or an optionally substituted straight or branched C₁₋₆ aliphatic chain wherein up to two carbon units of Z^(C) are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR^(C)—, —CONR^(C)NR^(C)—, —CO₂—, —OCO—, —NR^(C)CO₂—, —O—, —NR^(C)CONR^(C)—, —OCONR^(C)—, —NR^(C)NR^(C), —NR^(C)NR^(C)CO—, —NR^(C)CO—, —S—, —SO—, —SO₂—, —NR^(C)—, —SO₂NR^(C)—, —NR^(C)SO₂—, or —NR^(C)SO₂NR^(C)—.

Each R_(g) is independently R^(C), halo, —OH, —NH₂, —NO₂, —CN, —CF₃, or —OCF₃.

Each R^(C) is independently hydrogen, an optionally substituted C₁₋₈ aliphatic group; an optionally substituted 3-8 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an optionally substituted 8-12 membered fully saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R^(C) are taken together with the atom(s) to which they are attached to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each of which is optionally substituted with 1 to 3 substituents.

In several embodiments, R₃, R₄ and the nitrogen atom to which they are attached form an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic or bicyclic heterocycloaliphatic. In several embodiments, the heterocycloaliphatic formed from the R₃, R₄ and the nitrogen atom to which they are attached is substituted with 1-3 substituents.

In several embodiments, R₃, R₄ and the nitrogen atom to which they are attached form an optionally substituted monocyclic heterocycloaliphatic with 1-3 heteroatoms selected from N, O, and S. In another example R₃, R₄ and the nitrogen atom to which they are attached form a fully saturated optionally substituted heterocycloaliphatic (e.g., heterocycloalkyl). In yet another example, R₃, R₄, and the nitrogen atom to which they are attached form an optionally substituted morpholinyl, thiomorpholinyl, piperadinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, or imidazolinyl. In several embodiments the fully saturated heterocycloaliphatic formed by R₃, R₄, and the nitrogen atom to which they are attached is substituted with 1-3 substituents selected from halo, cyano, hydroxy, or optionally substituted C₁₋₅ aliphatic, heterocycloaliphatic, alkoxy, alkoxycarbonyl, alkylaminocarbonyl, or aralkyl. In several embodiments, the heterocycloaliphatic formed from R₃, R₄, and the nitrogen atom to which they are attached is a piperadinyl that is substituted with aliphatic, cycloaliphatic, alkoxy, alkoxycarbonyl, heterocycloaliphatic, cycloaliphatic, heteroaralkyl or aralkyl; or it is an unsubstituted piperadinyl. For example, the piperadinyl formed from R₃, R₄ and the nitrogen atom to which they are attached is substituted with methyl, pyrrolidinyl, cyclopentyl, phenylmethyl, or pryridinylmethyl. In some embodiments, R₃, R₄, and the nitrogen atom to which they are attached form unsubstituted morpholinyl, thiomorpholinyl, piperadinyl, piperazinyl, pyrrolidinyl, or tetrahydrofuranyl. In some embodiments, R₃, R₄, and the nitrogen atom to which they are attached form an alkyl substituted piperazinyl or morpholinyl. For example, R₃, R₄, and the nitrogen atom to which they are attached form a piperazinyl or morpholinyl that is optionally substituted with 1-2 alkyl groups. In other examples, R₃, R₄, and the nitrogen atom to which they are attached form a piperazinyl or a morpholinyl, each of which is substituted with 1-2 alkyl groups.

In several embodiments, R₃, R₄, and the nitrogen atom to which they are attached form an optionally substituted fully saturated or partially unsaturated bicyclic heterocycloaliphatic. For example, the bicyclic heterocycloaliphatic formed from R₃, R₄, and the nitrogen atom to which they are attached has 1-3 heteroatoms selected from N, O, and S. In other embodiments, the heterocycloaliphatic formed by R₃, R₄, and the nitrogen atom to which they are attached is substituted with 1-3 substituents. In other embodiments, R₃, R₄, and the nitrogen atom to which they are attached form an optionally substituted decahydroquinaolinyl, tropane, or octahydroindolyl. In several embodiments, R₃, R₄, and the nitrogen atom to which they are attached form an unsubstituted decahydroquinaolinyl. In several other embodiments, R₃, R₄, and the nitrogen atom to which they are attached form a decahydroquinolinyl that is optionally substituted with 1-2 methyl groups.

In several embodiments, R₃, R₄, and the nitrogen atom to which they are attached form an optionally substituted 6-10 membered heteroaryl. For example, the heteroaryl formed by R₃, R₄, and the nitrogen atom to which they are attached is substituted with 1-3 substituents. The optionally substituted heteroaryl formed by R₃, R₄, and the nitrogen atom to which they are attached is a monocyclic or bicyclic ring system. In several embodiments, R₃, R₄, and the nitrogen atom to which they are attached form optionally substituted 1,2,3,4-tetrahydroquinolinyl, or octahydroisoindolyl. In another embodiment, R₃, R₄, and the nitrogen atom to which they are attached form unsubstituted 1,2,3,4-tetrahydroquinolinyl, or octahydroisoindolyl.

In several embodiments, one of R₃ or R₄ is an optionally substituted 6-10 membered monocyclic or bicyclic aryl. In another example, R₃ or R₄ is substituted with 1-3 substituents. In some embodiments, R₃ or R₄ is an optionally substituted monocyclic aryl. For example R₃ or R₄ is a monocyclic aryl substituted with 1-3 of halo, cyano, hydroxy, methyl, alkoxy, alkoxycarbonyl, C₁₋₆ aliphatic, aminocarbonyl, or combinations thereof. In other examples, R₃ or R₄ is a phenyl. In several embodiments, R₃ or R₄ is an optionally substituted bicyclic aryl. In several embodiments, R₃ or R₄ is an optionally substituted naphthyl or indenyl. In several embodiments, R₃ or R₄ is substituted with 1-3 substituents. For example, R₃ or R₄ is substituted with 1-3 substituents selected from halo, cyano, hydroxy, alkoxy, alkoxycarbonyl, alkylaminocarbonyl, C₁₋₄ aliphatic, aryl or heteroaryl. In other examples, R₃ or R₄ is an unsubstituted naphthyl or indenyl.

In several embodiments R₃ or R₄ is an optionally substituted straight or branched C₁₋₈ aliphatic. For example, R₃ or R₄ is optionally substituted straight (e.g., methyl, ethyl, propyl, butyl, or the like) or branched (e.g., isopropyl, isobutyl, sec-propyl, sec-butyl or the like) aliphatic. For example, R₃ or R₄ is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl, each substituted with 1-3 substituents (e.g., 1-2 substituents). In other examples, R₃ or R₄ is an isopropyl or sec-propyl that is optionally substituted with 1-3 substituents (e.g., 1-2 substituents), or R₃ or R₄ is an unsubstituted sec-propyl or isopropyl. In several embodiments, R₃ or R₄ is unsubstituted methyl, ethyl, propyl, butyl, pentyl, or hexyl. In other embodiments, R₃ or R₄ is a —C(O)OH substituted aliphatic (e.g., alkyl-C(O)OH). For example, R₃ or R₄ is a methyl, ethyl, or propyl, each of which is substituted with —C(O)OH. In several embodiments, R₃ or R₄ is substituted with 1-2 substituents including halo, cyano, hydroxy, or optionally substituted cycloaliphatic, heterocycloaliphatic, aryl, alkoxy, haloalkylaryl, bicycloaliphatic, aryloxy, haloaryl, alkylamino, heteroaryl, cycloaliphatic, heterocycloaliphaticpropyl, isopropyl, or combinations thereof. In other embodiment, R₃ or R₄ is methyl, ethyl, or propyl that is substituted with a monocyclic optionally substituted aryl. For example, R₃ or R₄ is methyl, ethyl, or propyl that is substituted with alkoxyphenyl, cycloaliphaticphenyl, haloalkylphenyl, cyanophenyl, halophenyl, or hydroxyphenyl. In other embodiments, R₃ or R₄ is methyl, ethyl, or propyl that is substituted with a bicyclic aryl. For example R₃ or R₄ is methyl, ethyl, or propyl that is substituted with unsubstituted naphthyl or indenyl. In other embodiments, R₃ or R₄ is substituted with two substituents independently selected from halo, cyano, hydroxyl, aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, or alkoxy. In some embodiments, R₃ or R₄ is methyl substituted with aliphatic and aryl. In several embodiments, R₃ or R₄ includes an optionally substituted partially unsaturated aliphatic (e.g., alkenyl or alkynyl). In several examples, R₃ or R₄ includes optionally substituted ethenyl, propenyl, or butenyl. In other embodiments, R₃ or R₄ includes unsubstituted propenyl.

In several embodiments, R₃ or R₄ is an optionally substituted heteroaryl. For example R₃ or R₄ is an optionally substituted 6-10 membered monocyclic or bicyclic heteroaryl. In some examples, R₃ or R₄ is a monocyclic heteroaryl optionally substituted with 1-3 substituents. In other examples, R₃ or R₄ is a substituted pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl. In other examples R₃ or R₄ is an unsubstituted pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl. In several embodiments, R₃ or R₄ is an optionally substituted bicyclic heteroaryl. For example, R₃ or R₄ is a bicyclic heteroaryl substituted with 1-3 substituents. In other examples, R₃ or R₄ is an optionally substituted isoindolinyl. In some embodiments, R₃ or R₄ is unsubstituted isoindolinyl.

In several embodiments, R₃ or R₄ is an optionally substituted monocyclic or bicyclic cycloaliphatic. In some embodiments, R₃ or R₄ is a monocyclic cycloaliphatic optionally substituted with 1-3 substituents including hydroxy, alkoxy, alkylamino, alkyl carbonyl, aliphatic, halo, or combinations thereof. In other embodiments, R₃ or R₄ is optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. For example, R₃ or R₄ is unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In other embodiments, R₃ or R₄ is optionally substituted bicycloaliphatic. In several examples, R₃ or R₄ is bicycloaliphatic or bridged bicycloaliphatic optionally substituted with 1-3 substituents selected from hydroxy, alkoxy, alkylamino, alkyl carbonyl, aliphatic, and halo. In other examples, R₃ or R₄ is optionally substituted bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl, or bicyclo[2.2.1]heptyl. In other examples R₃ or R₄ is unsubstituted bicyclo[2.1.1]hexyl, or bicyclo[2.2.1]heptyl.

In several embodiments, R₃ or R₄ is hydrogen.

In several embodiments, each R₃, R₄, is independently selected from: hydrogen, methyl, ethyl,

In several embodiments, R₃, R₄, and the nitrogen atom to which they are attached is one selected from:

3. Substituent X

Each X is defined by —Z^(A)R₆, wherein Z^(A) is independently a bond or an optionally substituted branched or straight C₁₋₆ aliphatic chain wherein up to two carbon units of Z^(A) are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR^(A)—, —CONR^(A)NR^(A)—, —CO₂—, —OCO—, —NR^(A)CO₂—, —O—, —NR^(A)CONR^(A)—, —OCONR^(A)—, —NR^(A)NR^(A), —NR^(A)NR^(A)CO—, —NR^(A)CO—, —S—, —SO—, —SO₂—, —NR^(A)—, —SO₂NR^(A)—, —NR^(A)SO₂—, or —NR^(A)SO₂NR^(A)—.

Each R₆ is independently R^(A), halo, —OH, —NH₂, —NO₂, —CN, —CF₃, or —OCF₃.

Each R^(A) is independently hydrogen, an optionally substituted C₁₋₃ aliphatic group; a 3-8-membered optionally substituted fully saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an 8-12 membered optionally substituted fully saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R^(A) are taken together with the atom(s) to which they are attached to form an optionally substituted 3-12 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In several embodiments, X is a C₁₋₆ aliphatic that is optionally substituted and branched or straight. For example, X is an optionally substituted branched or straight C₁₋₆ aliphatic that is fully saturated or partially unsaturated. In other examples, X is fully saturated (e.g., alkyl). In some embodiments, X is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each of which is optionally substituted with 1-3 substituents. In other embodiments, X is an optionally substituted branched aliphatic. For example, X is an isopropyl, isobutyl, isopentane, sec-butyl, or sec-propyl, each of which is optionally substituted with 1-2 substituents. In several examples, X is an unsubstituted C₁₋₆ aliphatic. For example, X is unsubstituted methyl, ethyl, propyl, butyl, pentyl, or hexyl. In other embodiments, X is substituted with 1-3 substituents independently selected from alkylcarbonyl, alkoxy, —C(O)OH, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, and alkylamino. In several embodiments, X is optionally substituted C₁₋₆ aliphatic that is partially unsaturated. For example, X is an optionally substituted C₁₋₆ aliphatic that has at least 1 C—C double bond, or at least 1 C—C triple bond. In other examples, X is optionally substituted ethenyl, propenyl, but-1-enyl, or but-2-enyl. In some embodiments, X is substituted with 1-3 substituents independently selected from alkylcarbonyl, alkoxy, —C(O)OH, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, and alkylamino. In other embodiments, X is ethenyl substituted with —C(O)OH (e.g., acrylic acid).

In several embodiments, X is an optionally substituted C₁₋₆ alkoxy. The alkyl group of the alkoxy can be optionally substituted with 1-3 substituents. For example, X is methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy, each of which is optionally substituted. In other examples, X is prop-2-oxy, but-2-oxy, pent-2-oxy, or pent-3-oxy, each of which is optionally substituted. In several embodiments, X is unsubstituted prop-2-oxy, but-2-oxy, pent-2-oxy, or pent-3-oxy. In other examples, X is substituted with a C₁₋₃ aliphatic group. For example, X is ethoxy, propoxy, butoxy, pentoxy, or hexoxy, each of which is substituted with methyl or ethyl.

In several embodiments, X is an optionally substituted ring system that that is fully saturated, partially unsaturated, or fully unsaturated and attaches to the core phenyl with an oxy (—O—) group. In several examples, X is selected from optionally substituted aryloxy, heteroaryloxy, cycloaliphaticoxy, or heterocycloaliphaticoxy. In several embodiments, X is an unsubstituted aryloxy, heteroaryloxy, cycloaliphaticoxy, or heterocycloaliphaticoxy. For example, X is an unsubstituted phenoxy. In other embodiments, X is a phenoxy that is substituted with 1-3 substituents selected from halo, —CF₃, alkoxy, alkylcarbonyl, and cyano.

In several embodiments, X is an optionally substituted amino. For example X is substituted with 1-3 substituents selected from aliphatic, alkoxy, alkylsulfonyl, alkylcarbonyl, aryl, heteroaryl, cycloaliphatic, and heterocycloaliphatic. In several examples, X is alkylcarbonylamino.

In several embodiments, X is a halo (e.g., F, Cl, Br, or I).

In several embodiments, each X is independently selected from: halo,

4. Substituents Y and n

Each Y is hydrogen, or optionally substituted methyl.

Each n is 1-4.

In several embodiments, Y is methyl.

In several embodiments, n is 1 or 2.

5. Exemplary Compound Families

Another aspect of the present invention includes compounds of formula Ia:

or a pharmaceutically acceptable salt thereof, where R₁, R₂, R₃, R₄, X and n are defined above.

In several embodiments of formula Ia, when R₁ is alkyl, R₂ is not 3,5-bis-trifluoromethyl-phenyl-alkyl; when R₁ and R₂ together form pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted with —CH₃ or —CH₂CH₃, then X is not m-methyl, o-halo, p-aryl, or p-cyano; when R₁ or R₂ are aliphatic or alkoxyalkyl, then X is not m-methyl, o-halo, p-aryl, or p-cyano; and when R₁ is phenylmethyl optionally substituted with 1-2 —CH₃ groups or cycloaliphatic, and R₂ is one selected from substituted methyl, ethyl, and isopropyl, then

-   -   (1) R₃ together with R₄ form pyrrolidinyl, morpholinyl,         piperidinyl optionally substituted with aliphatic,         aminocarbonyl, or alkylcarbonyl, or one of R₃ or R₄ is         phenylmethyl, methylfuranyl, or methoxypropyl, and     -   (2) X is not m-methyl, p-aryl, o-halo or p-cyano.

In other embodiments of formula Ia, R₃ or R₄ is heterocycloaliphatic, bicycloaryl, bicycloheteroaliphatic, bicycloheteroaryl, heterocycloalkenyl, cycloaliphatic, alkenyl, 5-membered heterocycloaliphatic, heteroaralkyl, or bicycloaralkyl, each of which is optionally substituted; or one of R₃ and R₄ is hydrogen, R₃ or R₄ is alkyl substituted with cycloaliphatic, heteroaryl, heterocycloaliphatic, cyano, alkoxycarbonyl, —C(O)OH, guanidinylalkyl, bicycloaryl, halo, or alkoxy, or R₃ together with R₄ form a ring system selected from thiomorpholinyl, bicycloheteroaryl, bicyclic heterocycloaliphatic, 5-membered heterocycloaliphatic, and 6-membered heterocycloalkenyl, provided that when R₁ and R₂ together form pyrrolidinyl, morpholinyl, piperidinyl, each optionally substituted with —CH₃ or —CH₂CH₃, then X is not one selected from m-methyl, o-halo, p-aryl, and p-cyano; when R₁ and R₂ are aliphatic or alkoxyalkyl, then X is not one selected from m-methyl, o-halo, p-aryl, and p-cyano; and

-   -   (1) when R₁ is phenylmethyl optionally substituted with 1-2 —CH₃         groups or cycloaliphatic, and R₂ is one selected from         unsubstituted methyl, ethyl, and isopropyl, then R₃ together         with R₄ must form pyrrolidinyl, morpholinyl, piperidinyl         optionally substituted with aliphatic, aminocarbonyl, or         alkylcarbonyl; or one of R₃ and R₄ is phenylmethyl,         methylfuranyl, or methoxypropyl, and     -   (2) X is not o-halo or p-cyano.

Another aspect of the present invention includes compounds of formula II:

or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, X, n, and Y are defined above.

Each V is one selected from —CH—, —CH₂—, —N—, —O—, and —S—.

Each m is 1 or 2.

Each R₉ and R₁₀ are defined by —Z^(D)R₁₄, wherein each Z^(D) is independently a bond or an optionally substituted straight or branched C₁₋₆ aliphatic chain wherein up to two carbon units of Z^(D) are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR^(D)—, —CONR^(D)NR^(D)—, —CO₂—, —OCO—, —NR^(D)CO₂—, —O—, —NR^(D)CONR^(D)—, —OCONR^(D)—, —NR^(D)NR^(D), —NR^(D)NR^(D)CO—, —NR^(D)CO—, —S—, —SO—, —SO₂—, —NR^(D)—, —SO₂NR^(D)—, —NR^(D)SO₂—, or —NR^(D)SO₂NR^(D)—.

Each R₁₄ is independently R^(D), halo, —OH, —NH₂, —NO₂, —CN, —CF₃, or —OCF₃.

Each R^(D) is independently hydrogen, or an optionally substituted C₁₋₈ aliphatic group, an optionally substituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R^(D) are taken together with the atom(s) to which they are attached form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each of which is optionally substituted with 1 to 3 substituents.

In several embodiments of formula U, when R₁ or R₂ is 3,5-bis-trifluoromethylphenylmethyl, ring A together with R₉ and R₁₀ is not piperazinyl, optionally substituted piperidinyl, morpholinyl, or imidazolyl; when R₁ and R₂ together form pyrrolidinyl, morpholinyl, piperidinyl, each optionally substituted with —CH₃ or —CH₂CH₃, then X is not m-methyl, o-halo, p-aryl, and p-cyano; when R₁ and R₂ are aliphatic or alkoxyalkyl, then X is not from m-methyl, o-halo, p-aryl, and p-cyano; and when R₁ is phenylmethyl optionally substituted with 1-2 —CH₃ groups or cycloaliphatic, and R₂ is one selected from unsubstituted methyl, ethyl, and isopropyl, then

-   -   (1) ring B must form pyrrolidinyl, morpholinyl, piperidinyl         optionally substituted with aliphatic, or aminocarbonyl, or         alkylcarbonyl, and     -   (2) X is not o-halo, p-aryl, m-alkyl, or p-cyano.

Each R₉ and R₁₀ is hydrogen, halo, hydroxy, cyano, or C₁₋₆ aliphatic, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloaliphatic, or heterocycloaliphatic, each of which is optionally substituted with 1-3 substituents; or R₉ and R₁₀ together with the atom(s) to which they are attached form a 5-6 membered ring that is optionally substituted with 1-3 substituents.

In several embodiments, R₉ or R₁₀ is an optionally substituted C₁₋₆ aliphatic. For example, R₉ or R₁₀ is an optionally substituted straight or branched C₁₋₆ aliphatic. For example, R₉ or R₁₀ is optionally substituted straight (e.g., methyl, ethyl, propyl, butyl, or the like) or branched (e.g., isopropyl, isobutyl, sec-propyl, sec-butyl or the like) aliphatic. For example, R₉ or R₁₀ is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl, each substituted with 1-3 substituents. In other examples, R₉ or R₁₀ is an isopropyl or sec-propyl that is optionally substituted with 1-2 substituents, or R₉ or R₁₀ is an unsubstituted sec-propyl or isopropyl. In several embodiments, R₉ or R₁₀ is unsubstituted methyl, ethyl, propyl, butyl, pentyl, or hexyl. In other embodiments, R₉ or R₁₀ is a —C(O)OH substituted aliphatic (e.g., hydroxycarbonylalkyl). For example, R₉ or R₁₀ is a methyl, ethyl, or propyl, each of which is substituted with —C(O)OH. In several embodiments, R₉ or R₁₀ is substituted with halo, cyano, hydroxy, or optionally substituted cycloaliphatic, heterocycloaliphatic, aryl, alkoxy, haloalkylaryl, bicycloaliphatic, aryloxy, haloaryl, alkylamino, heteroaryl, cycloaliphatic, or heterocycloaliphatic. In other embodiment, R₉ or R₁₀ is methyl, ethyl, or propyl that is substituted with a monocyclic optionally substituted aryl. For example, R₉ or R₁₀ is methyl, ethyl, or propyl that is substituted with alkoxyphenyl, cycloaliphaticphenyl, haloalkylphenyl, cyanophenyl, halophenyl, or hydroxyphenyl. In other embodiments, R₉ or R₁₀ is methyl, ethyl, or propyl that is substituted with a bicyclic aryl. For example R₉ or R₁₀ is methyl, ethyl, or propyl that is substituted with unsubstituted naphthyl or indenyl. In other embodiments, R₉ or R₁₀ is di-substituted with two substituents independently selected from halo, cyano, hydroxyl, aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, or alkoxy. In some embodiments, R₉ or R₁₀ is methyl substituted with aliphatic and aryl. In several embodiments, R₉ or R₁₀ includes an optionally substituted partially unsaturated aliphatic (e.g., alkenyl or alkynyl). In several examples, R₉ or R₁₀ includes optionally substituted ethenyl, propenyl, or butenyl. In other embodiments, R₉ or R₁₀ includes unsubstituted methyl or propenyl.

In several embodiments, R₉, R₁₀, and the atom(s) to which they are attached form a 5-6 membered ring that is optionally substituted with 1-3 substituents. For example, R₉ and R₁₀ are attached to different carbon atoms and together with the carbon atoms form an optionally substituted 5-6 membered ring that is fused to ring A of formula II. In some embodiments, R₉, R₁₀, and the carbon atoms to which they are attached form an optionally substituted fully saturated, partially unsaturated, or fully unsaturated ring that is optionally substituted. In some embodiments, R₉, R₁₀, and the carbon atoms to which they are attached form a fully saturated 5-6 membered ring that is optionally substituted. For example, R₉, R₁₀, and the carbon atoms to which they are attached form a 5-6 membered cycloalkyl or heterocycloalkyl that is optionally substituted. In some embodiments, R₉, R₁₀, and the carbon atoms to which they are attached form an optionally substituted cyclohexyl or cyclopentyl ring that is fused to ring A. For example, R₉, R₁₀, and the carbon atoms to which they are attached form an unsubstituted cyclohexyl that is fused to ring A to create an unsubstituted decahydroquinolinyl or octahydroindolyl. In another embodiment, R₉, R₁₀, and the carbon atoms to which they are attached form an unsubstituted cyclopentyl that is fused to ring A to create an unsubstituted octahydrocyclopenta[b]pyridinyl or octahydrocyclopenta[b]pyrrolyl. In other embodiments, R₉, R₁₀, and the carbon atoms to which they are attached form a cycloalkyl ring that is fused to ring A and substituted with halo, aliphatic, alkoxy, cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl. In some embodiments, R₉, R₁₀, and the carbon atoms to which they are attached form an optionally substituted aryl ring that is fused to ring A. For example, R₉, R₁₀, and the carbon atoms to which they are attached form an optionally substituted phenyl that is fused to ring A to form a substituted or unsubstituted 1,2,3,4-tetrahydroquinolinyl or indolinyl.

In several embodiments, R₉ or R₁₀ is an optionally substituted alkoxy. For example, the aliphatic chain of the alkoxy can be straight or branched and substituted at any chemically feasible position. In some embodiments, R₉ or R₁₀ is an optionally substituted methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy. In other embodiments, R₉ or R₁₀ is unsubstituted.

In several embodiments, R₉ or R₁₀ is an optionally substituted alkoxy carbonyl. For example, the aliphatic chain of the alkoxy can be straight or branched and substituted at any chemically feasible position. In some embodiments, R₉ or R₁₀ is an optionally substituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, or hexoxycarbonyl.

In several embodiments, R₉ or R₁₀ is an optionally substituted monocyclic or bicyclic cycloaliphatic. In some embodiments, R₉ or R₁₀ is a monocyclic cycloaliphatic optionally substituted with 1-3 substituents selected from hydroxy, alkoxy, alkylamino, alkyl carbonyl, aliphatic, and halo. In other embodiments, R₉ or R₁₀ is optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. For example, R₉ or R₁₀ is unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In other embodiments, R₉ or R₁₀ is optionally substituted bicycloaliphatic. In several examples, R₉ or R₁₀ is bicycloaliphatic optionally substituted with 1-3 substituents selected from hydroxy, alkoxy, alkylamino, alkyl carbonyl, aliphatic, and halo. In other examples, R₉ or R₁₀ is optionally substituted bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, or bicyclo[2.2.1]heptane. In other examples, R₉ or R₁₀ is unsubstituted bicyclo[2.1.1]hexyl, or bicyclo[2.2.1]heptyl.

In several embodiments, R₉ or R₁₀ is an optionally substituted monocyclic or bicyclic heterocycloaliphatic including 1-3 heteroatoms selected from N, O, and S. In one group of examples, R₉ or R₁₀ is fully saturated or partially unsaturated. In one group of examples, R₉ or R₁₀ is an optionally substituted fully saturated monocyclic heterocycloaliphatic. In another group of examples, R₉ or R₁₀ is morpholinyl, pyrroldinyl, thiomorpholinyl, tetrahydro-2H-pyranyl, or tetrahydrothiophenyl, each optionally substituted with 1-3 substituents. In another group of examples, R₉ or R₁₀ is unsubstituted morpholinyl, pyrrolidinyl, thiomorpholinyl, tetrahydro-2H-pyranyl, or tetrahydrothiophenyl. In another group of examples, R₉ or R₁₀ is an unsubstituted tropane.

In several examples of compounds of formula II, when R₉ and R₁₀ are hydrogen, neither R₁ nor R₂ are H, —CH₃, or —CH₃C₆H₅.

Another aspect of the present invention includes compounds of formula III:

or a pharmaceutically acceptable salt thereof, wherein R₃, R₄, X, Y, and n are defined above; and

Each U is one selected from —CH—, —CH₂—, —N—, —O—, and —S—.

Each p is 1 or 2.

Each R₁₂ and R₁₃ are defined by —Z^(E)R₁₅, wherein each Z^(E) is independently a bond or an optionally substituted straight or branched C₁₋₆ aliphatic chain wherein up to two carbon units of Z^(C) are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR^(E)—, —CONR^(E)NR^(E)—CO₂—, —OCO—, —NR^(E)CO₂—, —O—, —NR^(E)CONR^(E)—, —OCONR^(E)—, —NR^(E)NR^(E), —NR^(E)NR^(E)CO—, —NR^(E)CO—, —S—, —SO—, —SO₂—, —NR^(E)—, —SO₂NR^(E)—, —NR^(E)SO₂—, or —NR^(E)SO₂NR^(E)—.

Each R₁₅ is independently R^(E), halo, —OH, —NH₂, —NO₂, —CN, —CF₃, or —OCF₃.

Each R^(E) is independently hydrogen, an optionally substituted C₁₋₈ aliphatic group, an optionally substituted 3-8 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an optionally substituted 8-12 membered fully saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R^(E) are taken together with the atom(s) to which they are attached to form an optionally substituted 3-12 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each of which is optionally substituted with 1 to 3 substituents.

In some embodiments of formula III, when ring B is pyrrolidinyl, morpholinyl, piperidinyl, and R₁₂ or R₁₃ is —CH₃ or —CH₂CH₃, then X is not m-methyl, o-halo, p-aryl, or p-cyano.

Each R₁₂ and R₁₃ is hydrogen, halo, hydroxy, cyano, or C₁₋₄ aliphatic, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloaliphatic, or heterocycloaliphatic, each of which is optionally substituted with 1-3 substituents; or R₁₂ and R₁₃ together with the atom(s) to which they are attached form a 5-6 membered ring that is optionally substituted with 1-3 substituents.

In several embodiments, R₁₂, R₁₃, and the atom(s) to which they are attached form a 5-6 membered ring that is optionally substituted with 1-3 substituents. For example, R₁₂ and R₁₃ are attached to different carbon atoms and together with the carbon atoms form an optionally substituted 5-6 membered ring that is fused to ring B of formula III. In some embodiments, R₁₂, R₁₃, and the carbon atoms to which they are attached form an optionally substituted fully saturated, partially unsaturated, or fully unsaturated ring that is optionally substituted. In some embodiments, R₁₂, R₁₃, and the carbon atoms to which they are attached form a fully saturated 5-6 membered ring that is optionally substituted. For example, R₁₂, R₁₃, and the carbon atoms to which they are attached form a 5-6 membered cycloalkyl or heterocycloalkyl that is optionally substituted. In some embodiments, R₁₂, R₁₃, and the carbon atoms to which they are attached form an optionally substituted cyclohexyl or cyclopentyl ring that is fused to ring B. For example, R₁₂, R₁₃, and the carbon atoms to which they are attached form an unsubstituted cyclohexyl that is fused to ring B to create an unsubstituted decahydroquinolinyl or octahydroindolyl. In another embodiment, R₁₂, R₁₃, and the carbon atoms to which they are attached form an unsubstituted cyclopentyl that is fused to ring B to create an unsubstituted octahydrocyclopenta[b]pyridinyl or octahydrocyclopenta[b]pyrrolyl. In other embodiments, R₁₂, R₁₃, and the carbon atoms to which they are attached form a cycloalkyl ring that is fused to ring B and is substituted with halo, aliphatic, alkoxy, cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl. In some embodiments, R₁₂, R₁₃, and the carbon atoms to which they are attached form an optionally substituted aryl ring that is fused to ring B. For example, R₁₂, R₁₃, and the carbon atoms to which they are attached form an optionally substituted phenyl that is fused to ring B to form a substituted or unsubstituted 1,2,3,4-tetrahydroquinolinyl or indolinyl. In other examples, R₁₂, R₁₃, and the carbon atoms to which they are attached form a mono- or di-substituted phenyl. In some embodiments, R₁₂, R₁₃, and the carbon atoms to which they are attached form a phenyl that is substituted with alkoxy (e.g., methoxy), aliphatic, alkylcarbonyl, or alkoxycarbonyl. In several examples, R₁₂, R₁₃, and the carbon atoms to which they are attached form a phenyl substituted with 1-2 methoxy groups that is fused to ring B.

In several embodiments, R₁₂ or R₁₃ is optionally substituted aryl. For example, R₁₂ or R₁₃ is aryl substituted with 1-2 substituents. In other examples, R₁₂ or R₁₃ is aryl substituted with aliphatic, halo, hydroxy, cyano, aryl, alkoxy, alkylcarbonyl, or alkoxycarbonyl. In several examples, R₁₂ or R₁₃ is unsubstituted.

In several examples, R₁₂ or R₁₃ is an optionally substituted alkoxy. For example, R₁₂ or R₁₃ is optionally substituted C₁₋₆-alkoxy. In several examples, R₁₂ or R₁₃ is optionally substituted methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy. In several other examples, R₁₂ or R₁₃ is substituted with aliphatic, aryl, heteroaryl, cycloaliphatic, or heterocycloaliphatic. In several embodiments, R₁₂ or R₁₃ is unsubstituted methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy.

In several embodiments, R₁₂ or R₁₃ is optionally substituted alkylcarbonyl. For example, R₁₂ or R₁₃ is optionally substituted C₁₋₆-alkyl-carbonyl. Other examples include methylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcarbonyl, or hexylcarbonyl, each of which is optionally substituted with 1-2 substituents. In several embodiments, R₁₂ or R₁₃ is substituted with aliphatic, amino, hydroxyl, aryl, or heteroaryl. In several embodiments, R₁₂ or R₁₃ is unsubstituted methylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcarbonyl, or hexylcarbonyl.

In several embodiments, R₁₂ or R₁₃ is an optionally substituted C₁₋₆ aliphatic. For example, R₁₂ or R₁₃ is an optionally substituted straight or branched C₁₋₆ aliphatic. For example, R₁₂ or R₁₃ is optionally substituted straight (e.g., methyl, ethyl, propyl, butyl, or the like) or branched (e.g., isopropyl, isobutyl, sec-propyl, sec-butyl or the like) aliphatic. For example, R₁₂ or R₁₃ is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl, each substituted with 1-3 substituents. In other examples, R₁₂ or R₁₃ is an isopropyl or sec-propyl that is optionally substituted with 1-2 substituents, or R₁₂ or R₁₃ is an unsubstituted sec-propyl or isopropyl. In several embodiments, R₁₂ or R₁₃ is unsubstituted methyl, ethyl, propyl, butyl, pentyl, or hexyl. In other embodiments, R₁₂ or R₁₃ is a —C(O)OH substituted aliphatic (e.g., alkyl-C(O)OH). For example, R₁₂ or R₁₃ is a methyl, ethyl, or propyl, each of which is substituted with —C(O)OH. In several embodiments, R₁₂ or R₁₃ is substituted with halo, cyano, hydroxy, or optionally substituted cycloaliphatic, heterocycloaliphatic, aryl, alkoxy, haloalkylaryl, bicycloaliphatic, aryloxy, haloaryl, alkylamino, heteroaryl, cycloaliphatic, or heterocycloaliphatic. In other embodiment, R₁₂ or R₁₃ is methyl, ethyl, or propyl that is substituted with a monocyclic optionally substituted aryl. For example, R₁₂ or R₁₃ is methyl, ethyl, or propyl that is substituted with alkoxyphenyl, cycloaliphaticphenyl, haloalkylphenyl, cyanophenyl, halophenyl, or hydroxyphenyl. In other embodiments, R₁₂ or R₁₃ is methyl, ethyl, or propyl that is substituted with a bicyclic aryl. For example R₁₂ or R₁₃ is methyl, ethyl, or propyl that is substituted with unsubstituted naphthyl or indenyl. In other embodiments, R₁₂ or R₁₃ is di-substituted with two substituents independently selected from halo, cyano, hydroxyl, aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, or alkoxy. In some embodiments, R₁₂ or R₁₃ is methyl substituted with aliphatic and aryl. In several embodiments, R₁₂ or R₁₃ includes an optionally substituted partially unsaturated aliphatic (e.g., alkenyl or alkynyl). In several examples, R₁₂ or R₁₃ includes optionally substituted ethenyl, propenyl, or butenyl. In other embodiments, R₁₂ or R₁₃ includes unsubstituted methyl or propenyl.

In several examples of compounds of formulae Ia, II, or III:

When R₁ is alkyl, R₂ is not 3,5-bis-trifluoromethyl-phenyl-alkyl.

When R₁ and R₂ together form pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted with —CH₃ or —CH₂CH₃, then X is not m-methyl, o-halo, p-aryl, or p-cyano.

When each R₁ or R₂ is aliphatic or alkoxyalkyl, then X is not m-methyl, o-halo, p-aryl, and p-cyano.

When R₁ is phenylmethyl optionally substituted with 1-2 —CH₃ groups or cycloaliphatic, and R₂ is unsubstituted methyl, ethyl, or isopropyl, then R₃ together with R₄ must form pyrrolidinyl, morpholinyl, piperidinyl optionally substituted with aliphatic, aminocarbonyl, or alkylcarbonyl, or each R₃ or R₄ is phenylmethyl, methylfuranyl, or methoxypropyl, and X is not m-methyl, p-aryl, o-halo or p-cyano.

6. Examples of Compounds

Exemplary compounds of the present invention include, but are not limited to, those illustrated in Table 1 below.

TABLE 1 Examples of compounds of the present invention

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

III. Synthetic Scheme

Compounds of the invention can be synthesized by any conventional reactions known in the art. One method of syntheses is illustrated in Scheme 1 without limitation.

Referring to Scheme 1, R₅ is a C₁₋₅ alkyl. Reaction of the keto-ester b with a formamide dialkylacetal such as, for example, dimethylformamide dimethylacetal, provides the aminomethylene compound c. Reaction of d with 2-methylisothiourea sulfate in the presence of sodium acetate provides the thiopyrimidine e. Oxidation off with a suitable oxidizing reagent provides the sulfoxo-pyrimidine f. Suitable oxidizing reagents include, for example, m-chloroperbenzoic acid. Reaction off with the amine R₃R₄NH provides the 2-aminopyrimidine g. Hydrolysis of g with, for example, an alkaline earth hydroxide such as potassium hydroxide or sodium hydroxide, provides the acid g. Conversion of g to the amide a, compounds of the invention, can be achieved by converting the acid g first to an active acid derivative such as, for example, an acid chloride followed by reaction of the active derivative with the amine R₁R₂NH. Alternatively, the amide formation may be achieved by reaction of g with the amine R₁R₂NH in the presence of a suitable coupling reagent such as, for example, EDC or HATU. Acid addition salts such as, for example, a hydrochloride, may be prepared by reaction of the basic compound 1 with an acid in a solvent from which the salt will precipitate such as, for example, diethylether.

A variation of Scheme 1 is illustrated in Scheme 2 without limitation.

In reference to Scheme 2, the esterpyrimidine (Scheme 1) is converted to the corresponding amidepyrimidine h following procedures as described above for preparing the amides a. Oxidation of h and displacement of the sulfonyl group with HNR₃R₄ as previously described in scheme 1 provides the compounds of the invention a.

An alternative method for preparation of the compounds is illustrated in Scheme 3 without limitation.

Referring to Scheme 3, condensation of an aryl aldehyde with an acetoacetate ester and urea in the presence of a catalyst such as, for example, cuprous chloride and a Lewis acid such as, for example, borontrifluoride ethereate provides the dihydropyrimidinone j. Oxidation of h with, for example, 60% nitric acid gives the pyrimidinone k. Condensation of with an amine HNR₃R₄ in the presence of a condensation reagent such as, for example, PyBrop (Bromo-tris-pyrrolidino phosphoniumhexafluorophosphate) provides the aminopyridine f. Conversion off to the compounds of the invention can be achieved as described above in Scheme 1.

The amine intermediates HNR₁R₂ are commercially available, known in the art, or may be prepared by known reductive amination methods or condensation of the amine with an aryl halide using known methodology and as illustrated in the Examples herein.

An alternative method for preparation of the compounds is illustrated in Scheme 4 without limitation.

Referring to Scheme 4, the pyrimidinedione a′ is converted to the dichloropyrimidine b′ by reaction with phosphorous oxychloride in the presence of dimethylformamide. Coupling of b′ with an arylboronic acid in the presence of a palladium catalyst such as, for example, Pd₂(dba)₃ and a trialkylphosphine such as, for example, tri-t-butyl phosphine provides the aryl substituted pyrimidine c′. Displacement of the chloro group in c′ with the amine HNR₃R₄ provides the aminopyrimidine d′. Hydrolysis of the ester in d′ with, for example, sodium hydroxide in ethanol provides the corresponding acid which is converted to the compounds of the invention a using known amide forming conditions.

IV. Formulations, Administrations, and Uses

A. Pharmaceutically Acceptable Compositions

As discussed above, the present invention provides compounds that are inhibitors of voltage-gated sodium ion channels and/or calcium channels, and thus the present compounds are useful for the treatment of diseases, disorders, and conditions including, but not limited to acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, and incontinence. Accordingly, in another aspect of the present invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. As used herein, the term “inhibitorily active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of a voltage-gated sodium ion channel or calcium channel.

Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water, isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

B. Uses of Compounds and Pharmaceutically Acceptable Compositions

In yet another aspect, a method for the treatment or lessening the severity of acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, or cancer pain is provided comprising administering an effective amount of a compound, or a pharmaceutically acceptable composition comprising a compound to a subject in need thereof. In certain embodiments, a method for the treatment or lessening the severity of acute, chronic, neuropathic, or inflammatory pain is provided comprising administering an effective amount of a compound or a pharmaceutically acceptable composition to a subject in need thereof. In certain other embodiments, a method for the treatment or lessening the severity of radicular pain, sciatica, back pain, head pain, or neck pain is provided comprising administering an effective amount of a compound or a pharmaceutically acceptable composition to a subject in need thereof. In still other embodiments, a method for the treatment or lessening the severity of severe or intractable pain, acute pain, postsurgical pain, back pain, tinnitis or cancer pain is provided comprising administering an effective amount of a compound or a pharmaceutically acceptable composition to a subject in need thereof.

In certain embodiments of the present invention an “effective amount” of the compound or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of one or more of acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, tinnitis or cancer pain.

The compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, tinnitis or cancer pain. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form”, as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term “patient”, as used herein, means an animal, preferably a mammal, and most preferably a human.

The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The active compounds can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

As described generally above, the compounds of the invention are useful as inhibitors of voltage-gated sodium ion channels or calcium channels, preferably N-type calcium channels. In one embodiment, the compounds and compositions of the invention are inhibitors of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2, and thus, without wishing to be bound by any particular theory, the compounds and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 is implicated in the disease, condition, or disorder. When activation or hyperactivity of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2, is implicated in a particular disease, condition, or disorder, the disease, condition, or disorder may also be referred to as a “NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8 or NaV1.9-mediated disease, condition or disorder” or a “CaV2.2-mediated condition or disorder”. Accordingly, in another aspect, the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 is implicated in the disease state.

The activity of a compound utilized in this invention as an inhibitor of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 may be assayed according to methods described generally in the Examples herein, or according to methods available to one of ordinary skill in the art.

In certain exemplary embodiments, compounds of the invention are useful as inhibitors of NaV1.3. In other embodiments, compounds of the invention are useful as inhibitors of NaV1.3 and CaV2.2. In still other embodiments, compounds of the invention are useful as inhibitors of CaV2.2.

It will also be appreciated that the compounds and pharmaceutically acceptable compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated”. For example, exemplary additional therapeutic agents include, but are not limited to: nonopioid analgesics (indoles such as Etodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such as Nabumetone; oxicams such as Piroxicam; para-aminophenol derivatives, such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylates such as Asprin, Choline magnesium trisalicylate, Diflunisal; fenamates such as meclofenamic acid, Mefenamic acid; and pyrazoles such as Phenylbutazone); or opioid (narcotic) agonists (such as Codeine, Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol, Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesic approaches may be utilized in conjunction with administration of one or more compounds of the invention. For example, anesthesiologic (intraspinal infusion, neural blocade), neurosurgical (neurolysis of CNS pathways), neurostimulatory (transcutaneous electrical nerve stimulation, dorsal column stimulation), physiatric (physical therapy, orthotic devices, diathermy), or psychologic (cognitive methods-hypnosis, biofeedback, or behavioral methods) approaches may also be utilized. Additional appropriate therapeutic agents or approaches are described generally in The Merck Manual, Seventeenth Edition, Ed. Mark H. Beers and Robert Berkow, Merck Research Laboratories, 1999, and the Food and Drug Administration website, www.fda.gov, the entire contents of which are hereby incorporated by reference.

The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the present invention, in another aspect, includes a composition for coating an implantable device comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. In still another aspect, the present invention includes an implantable device coated with a composition comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. Suitable coatings and the general preparation of coated implantable devices are described in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.

Another aspect of the invention relates to inhibiting one or more of NaV1.1, NaV1.2, NaV1.3,NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 activity in a biological sample or a patient, which method comprises administering to the patient, or contacting said biological sample with a compound of formula I or a composition comprising said compound. The term “biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof, and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, the study of sodium ion channels in biological and pathological phenomena; and the comparative evaluation of new sodium ion channel inhibitors.

V. Preparations and Examples Preparation 1: N-Benzylcyclobutylamine

A sodium cyanoborohydride (0.88 g, 14 mmol) was added slowly to a stirred solution of benzaldehyde (0.71 g, 7.00 mmol) in methanol (9 mL) and glacial acetic acid (1 mL) at room temperature and the mixture was heated at 60° C. for 3 hr and cooled to room temperature. The solvent was evaporated under reduced pressure, and the crude material was dissolved in water and basified with a 2N NaOH solution (10 mL). The aqueous layer was extracted with EtOAc (3×50 mL), dried and concentrated. The residue was purified by Biotage SP1 on packed silica gel column (10%-80% EtOAc/Hexanes gradient) to give N-benzylcyclobutylamine (0.65 g, 58%). Mass Spec. FIA MS 312 (M+1), ¹H NMR (DMSO-d6, 500 MHz) δ 7.26-7.31 (m, 4H), 7.17-7.21 (d, 1H), 3.58 (s, 2H), 3.13 (m, 1H), 2.11 (brs, 1H), 2.04 (m, 2H), 1.50-1.69 (m, 4H).

Preparation 2: N-Isopropyl-3-methoxybenzenamine

To a microwave tube charged with a stirring bar was added sodium cyanoborohydride (0.10 g, 1.6 mmol) and m-anisidine (0.075 mL, 0.8 mmol) in methanol (1 mL). To this solution was the added acetone (0.5 mL) and glacial acetic acid (0.5 mL). Once the gas evolution had subsided, the tube was crimped and subjected to microwave irradiation at 130° C. for 15 minutes. The solution was diluted with CH₂Cl₂, washed once with 1N NaOH, and the organic layer was dried (Na₂SO₄), filtered and concentrated to a yellow liquid. This was purified via silica gel chromatography with an ethyl acetate/hexanes gradient (R_(f)=0.60 in 4:1 Hex/EtOAc) to give N-isopropyl-3-methoxybenzenamine as a colorless oil. FIA MS 166 (M+1).

Preparation 3: N-Cyclopropyl-3-methoxybenzenamine

To a high-pressure tube was added 3-bromoanisole (0.250 mL, 2 mmol), cyclopropylamine (0.225 mL, 3.2 mmol), sodium t-butoxide (0.29 g, 3.0 mmol), (+/−) BINAP (0.04 g, 0.06 mmol), and Pd₂(dba)₃ (0.010 g, 0.01 mmol). This mixture was suspended in 4 mL anhydrous toluene. The tube was flushed with dry nitrogen gas, then capped and wrapped in aluminum foil. The reaction mixture was stirred and heated to 80° C. overnight, then allowed to cool, and the reaction vessel was opened. The mixture was diluted with diethyl ether, filtered through Celite, and the filtrate was concentrated to a yellow oil. LC/MS analysis showed one peak with the correct mass, and due to the limited stability of the material, it was carried through without further purification. FIA MS 164 (M+1).

Example 1 4-(2-Fluoro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid benzyl-isopropyl-amide (Compound No. 326)

Synthesis of 4-(2-Fluoro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid benzyl-isopropyl-amide (Compound No. 326): i. DMF-DMA, toluene; ii. 2-methylisothiourea sulfate, NaOAc, DMF, 80-90° C., 60% over 2 steps; iii. m-CPBA, CH₂Cl₂, −78 to 0° C.; iv. morpholine, THF, reflux; v. 10 N aq. NaOH, MeOH, reflux, 74% over 3 steps; vi. 1) (COCl)₂, CH₂Cl₂; 2) Bn(i-Pr)NH, toluene, 92%; vii. HCl, Et₂O.

Step i. 3-Dimethylamino-2-(2-fluoro-benzoyl)-acrylic acid ethyl ester

A mixture of ethyl 3-(2-fluorophenyl)-3-oxopropanoate (14.29 g, 68.0 mmol) and DMF-DMA (12.15 g, 0.102 mol, 1.5 eq.) in toluene (50 mL) was refluxed for 2 hours and concentrated to give 3-dimethylamino-2-(2-fluoro-benzoyl)-acrylic acid ethyl ester as a red oil in quantitative yield.

Step ii: 4-(2-Fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester

3-Dimethylamino-2-(2-fluoro-benzoyl)-acrylic acid ethyl ester was dissolved in DMF (100 mL). To the solution was added isothiourea sulfate (18.92 g, 68.0 mmol) and NaOAc (23.24 g, 0.28 mol). The reaction mixture was heated at 80-90° C. overnight. Water was added to the cooled solution. The product was extracted with EtOAc (3×100 mL). The combined organic layers were washed with a saturated aqueous NaHCO₃ solution and water, dried over Na₂SO₄, and concentrated. The crude product was purified by column chromatography (1 L silica, EtOAc) to give 4-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester as a yellow oil (11.86 g, 40.6 mmol, 60% over 2 steps).

Step iii: 4-(2-Fluoro-phenyl)-2-methanesulfinyl-pyrimidine-5-carboxylic acid ethyl ester

A Na₂SO₄-dried solution of m-CPBA (10.64 g, ca. 45 mmol) in CH₂Cl₂ (100 mL) was added drop wise to a cold (−65° C.) solution of 4-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester in CH₂Cl₂ (200 mL) keeping the temperature below −65° C. The yellow suspension was allowed to warm to 0° C. over 1 hour. After 3 hours at 0° C., a saturated aqueous NaHCO₃ solution (100 mL) was added to quench the reaction. The organic layer was separated, washed with saturated aqueous NaCl solution, dried over Na₂SO₄, and concentrated. The product was taken up in CH₂Cl₂ and washed again with a saturated aqueous NaHCO₃ solution to remove traces of m-C(P)BA giving 4-(2-fluoro-phenyl)-2-methanesulfinyl-pyrimidine-5-carboxylic acid ethyl ester (12.86 g, >100%).

Step iv: 4-(2-Fluoro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid ethyl ester

Morpholine (7.0 mL, 6.9 g, 80 mmol) was added to a solution of 4-(2-fluoro-phenyl)-2-methanesulfinyl-pyrimidine-5-carboxylic acid ethyl ester in THF (80 mL). The resulting mixture was heated at reflux for 3 hours. Concentration of the solution afforded the product as a yellow oil. Traces of morpholine were removed at oil pump vacuum in a Kugelrohr apparatus to yield 4-(2-fluoro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid ethyl ester (16.00 g, >100%).

Step v: 4-(2-Fluoro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid

4-(2-Fluoro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid ethyl ester was dissolved in a mixture of methanol (150 mL) and a 33% aqueous NaOH solution (150 mL). The mixture was heated at reflux for 3 hours, and allowed to cool to room temperature overnight. The solution was concentrated to ca. half the volume under reduced pressure. The resulting suspension was adjusted to pH 7 with a 1-5N aqueous HCl solution. The formed precipitate was filtered off, washed with water (3×), and air-dried at 45° C. overnight to give 4-(2-fluoro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid as a tan solid (9.051 g, 29.8 mmol, 74% over 3 steps).

Step vi: 4-(2-Fluoro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid benzyl-isopropyl-amide

To an ice-cooled solution of 4-(2-fluoro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (4.321 g, 14.25 mmol) in CH₂Cl₂ (100 mL) and DMF (2 drops) was added oxalyl chloride (1.5 mL, 2.21 g, 17.5 mmol) dropwise. Most solids dissolved at first, later a precipitate formed. The suspension was stirred for 1 hour at 0° C., and then allowed to warm to room temperature (all solids dissolved). The solution was concentrated to a dark oil, which crystallized upon standing. The crude acid chloride was taken up in toluene (50 mL, distilled, dried over Na₂SO₄) and cooled in ice. N-Isopropylbenzylamine (9.5 mL, 8.5 g, 56.8 mmol) was added. The resulting suspension was stirred at room temperature for 90 minutes, washed with water and a saturated aqueous NaCl solution, dried over Na₂SO₄, and concentrated. The crude product was purified by column chromatography (400 mL silica, EtOAc/heptanes 1:1). All fractions containing the product were combined and concentrated. Some of the excess amine eluted with the product. A solution of the mixture in CH₂Cl₂ (50 mL) was washed with a 10% aqueous citric acid solution (2×25 mL), water (25.mL), and saturated aqueous NaCl solution (25 mL), dried over Na₂SO₄, and concentrated to give pure 4-(2-fluoro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid benzyl-isopropyl-amide as a yellowish foam (5.685 g, 13.08 mmol, 92%).

Step vii: 4-(2-Fluoro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid benzyl-isopropyl-amide HCl salt

To a solution of 4-(2-fluoro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid benzyl-isopropyl-amide in Et₂O (20 mL) was added 1N HCl in Et₂O (15 mL, 15 mmol). The resulting slurry was stirred vigorously for 1 hour. The solids were filtered off, washed with Et₂O (2×20 mL), and dried in vacuo (0.01 mbar) overnight to yield 4-(2-fluoro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid benzyl-isopropyl-amide HCl salt (5.70 g, 12.10 mmol, 93%).

Example 2 N-benzyl-N-cyclobutyl-4-(2-fluorophenyl)-2-morpholinopyrimidine-5-carboxamide (Compound No. 86)

A solution of 2M oxalyl chloride in CH₂Cl₂ (0.062 mL, 0.125 mmol) was added to a stirred solution of 4-(2-fluorophenyl)-2-morpholinopyrimidine-5-carboxylic acid (Example 1; 0.03 g, 0.1 mmol) in CH₂Cl₂(2 mL) and DMF (0.030 mL) at room temperature, and stirring continued for 15 min. A solution of N-benzylcyclobutanamine (0.016 g, 0.1 mmol) in CH₂Cl₂ (1 mL) and diisopropylethylamine (0.044 mL, 0.25 mmol) were added and stirred for 3 h. The solvent was removed under reduced pressure, and the residue was purified by Biotage SP1 on packed silica gel column (10%-80% EtOAc/Hexanes gradient) to give N-benzyl-N-cyclobutyl-442-fluorophenyl)-2-morpholinopyrimidine-5-carboxamide (0.032 g, 72%). Mass Spec. FIA MS 447 (M+1), NMR (DMSO-d6, 500 MHz) δ 8.43 (brs, 1H), 7.52-7.55 (m, 2H), 6.99-7.31 (m, 7H), 4.62 (brm, 2H), 3.78 (brm, 4H0, 3.68 (brm, 4H), 2.15 (brm, 2H), 1.85 (brm, 2H), 1.17 (brm, 2H).

Example 3

Following the procedures of Examples 1 and 2 making non-critical variations and using amines HNR₁R₂ prepared by the procedure of preparation 1 the following compounds were prepared.

TABLE 2 Exemplary compounds using amines prepared by the procedure of preparation 1. Compound No. 5 12 38 65 111 129 133 144 149 155 156 157 188 208 215 228 242 268 292 328 339 342

Example 4

Following the procedures of Examples 1 and 2 making non-critical variations and using amines HNR₁R₂ prepared by the procedure of preparation 2 the following compounds were prepared.

TABLE 3 Exemplary compounds using amines prepared by the procedure of preparation 2. Compound No. 4 8 14 19 20 29 41 47 53 62 63 74 91 94 95 101 102 116 119 127 128 131 135 142 152 153 159 161 162 170 172 177 190 196 200 210 212 213 219 222 224 230 244 247 249 252 256 258 263 265 267 294 297 300 320 322 325 327

Example 5

Following the procedures of Examples 1 and 2 making non-critical variations commonly known in the art and using amines HNR₁R₂ prepared by the procedure of preparation 3, Compound No. 31 was prepared.

Example 6

Additional compounds prepared following the above general procedures include those in Table 4.

TABLE 4 Exemplary compounds prepared using general procedures of Examples 1-5. Compound No. 6 7 11 13 23 25 34 36 45 46 57 59 64 75 76 80 85 85 103 107 112 115 117 120 122 137 158 174 187 192 194 195 203 207 260 266 275 277 287 295 296 304 306 310 314 316 326 331 340 346

Example 7 4-(2-fluorophenyl)-N-isopropyl-N-(3-methoxybenzyl)-2-(piperidin-1-yl)pyrimidine-5-carboxamide (Compound No. 20)

Synthesis of 4-(2-fluorophenyl)-N-isopropyl-N-(3-methoxybenzyl)-2-(piperidin-1-yl)pyrimidine-5-carboxamide (Compound No. 20). i. NaOH, water, MeOH, reflux, 1 h. ii. a. (COCl)₂, DMF, CH₂Cl₂, b. N-(3-methoxybenzyl)propan-2-amine, DIPEA MCPBA, CH2Cl2 iv piperidine, THF, heat

Steps i and ii: N-(3-Methoxybenzyl)-4-(2-fluorophenyl)-N-isopropyl-2(methylthio)pyrimidine-5-carboxamide

A mixture of ethyl 4-(2-fluorophenyl)-2-(methylthio)pyrimidine-5-carboxylate (3.3 g, 10.96 mmol), solid NaOH (3.2 g) in ethanol (30 mL) and water (6 mL) was refluxed for 1 h. and cooled to room temperature. The solvent was removed under reduced pressure, and the residue was acidified with 6N HCl. The product was extracted with EtOAC (3×50 mL), and the organic extracts were dried and concentrated to give crude acids (1.6 g). A solution of 2 M oxalyl chloride in CH₂Cl₂ (3.00 mL, 6 mmol) was added to a stirred solution of the crude acids (1.6 g) in CH₂Cl₂ (25 mL) and DMF (1 mL) at room temperature, and stirring continued for 15 min. A solution of N-(3-methoxybenzyl)propan-2-amine, (1.07 g, 6.00 mmol) in CH₂Cl₂ (2 mL) and diisopropylethylamine (2 mL, 12 mmol) was added and stirred for 1 hr. The solvent was removed under reduced pressure and the residue was purified by Biotage SP1 on packed silica gel column (10%-80% EtOAc/Hexanes gradient) to give N-(3-methoxybenzyl)-4-(2-fluorophenyl)-N-isopropyl-2(methylthio)pyrimidine-5-carboxamide (0.6 g, 13%). Mass Spec. FIA MS 426 (M+1).

Step iii: N-(3-Methoxybenzyl)-4-(2-fluorophenyl)-N-isopropyl-2-(methylsulphonyl)pyrimidine-5-carboxamide

70% of MCPBA (0.688 g, 2.80 mmol) was added to a stirred solution of N-(3-methoxybenzyl)-4-(2-fluorophenyl)-N-isopropyl-2(methylthio)pyrimidine-5-carboxamide (0.60 g, 1.41 mmol) in CH₂Cl₂ (10 mL), and the mixture was stirred at room temperature for 2 h. The solution was washed with saturated NaHCO₃, dried and concentrated. The solvent was removed under reduced pressure, and the residue was purified by Biotage SP1 on packed silica gel column (5%-40% MeOH/CH₂Cl₂ gradient) to give N-(3-methoxybenzyl)-4-(2-fluorophenyl)-N-isopropyl-2-(methylsulfonyl)pyrimidine-5-carboxamide (0.32 g, 49%). Mass Spec. FIA MS 463 (M+1).

Step iv: N-(3-Methoxybenzyl)-4-(2-fluorophenyl)-N-isopropyl-2-(piperidin-1-yl)pyrimidine-5-carboxamide (Compound No. 20)

Piperidine (0.0054 g, 0.064 mmol) was added to a stirred solution of N-(3-methoxybenzyl)-4-(2-fluorophenyl)-N-isopropyl-2-(methylsulfonyl)pyrimidine-5-carboxamide (0.015 g, 0.032 mmol) in THF (1 mL) and the mixture was heated at 80° C. for 1 h. The solvent was removed under reduced pressure, and the product was purified by preparative HPLC (5-80% CH₃CN/0.05% TFA gradient over 15 min) to give N-(3-methoxybenzyl)-4-(2-fluorophenyl)-N-isopropyl-2-(piperidin-1-yl)pyrimidine-5-carboxamide Compound No. 20 (0.012 g, 81%).

Example 8

Following the procedures of Example 7, and making non-critical variations, the following compounds in Table 5 were prepared.

TABLE 5 Exemplary compounds prepared by procedures of Example 7. Compound No. 2 3 9 17 21 24 35 44 50 67 69 84 89 92 113 114 134 139 151 164 165 189 204 218 226 229 235 238 246 250 255 270 274 279 284 288 308 311 312 313 321 323 332 335 336 351

Example 9 N-benzyl-4-(2-fluorophenyl)-N-isopropyl-6-methyl-2-morpholinopyrimidine-5-carboxamide (Compound No. 338)

Synthesis of N-benzyl-4-(2-fluorophenyl)-N-isopropyl-6-methyl-2-morpholinopyrimidine-5-carboxamide Compound No. 338: i. CuCl, BF₃OEt₂, THF, reflux, 18 h ii 60% HNO3, rt, 30 min iii PyBrop, morpholine, Et₃N, THF, RT, 2 h iv NaOH, water, EtOH v. a. (COCl₂, DMF, CH₂Cl₂ b. DIPEA, N-benzylpropan-2-amine, RT 16 h

Step i: Ethyl 4-(2-fluorophenyl)-1,2,3,4-tetrahydro-6-methyl-2-oxopyrimidine-5-carboxylate

A mixture of 2-fluorobenzaldehyde (5 g, 40.28 mmol), urea (3.8 g, 61 mmol), ethylacetoaceate (5.24 g, 40.28 mmol), CuCl (0.4 g, 4 mmol), BF₃OEt₂ (7 mL, 53 mmol), and glacial acetic acid (0.24 g, 4 mmol) in THF (80 mL) was refluxed for 18 h and then cooled to room temperature. The mixture was quenched with saturated NaHCO₃ (50 mL), and EtOAc (100 mL) was added. The layers were separated and the organic layer with a white suspension was evaporated to give a white solid. The solid was suspended in toluene (100 mL) and stirred for 2 days at room temperature. The solid was filtered, washed with ether, and dried to give ethyl 4-(2-fluorophenyl)-1,2,3,4-tetrahydro-6-methyl-2-oxopyrimidine-5-carboxylate (9.9 g, 88%). Mass Spec. FIA MS 279 (M+1).

Step ii: Ethyl 4-(2-fluorophenyl)-1,2-dihydro-6-methyl-2-oxopyrimidine-5-carboxylate

Ethyl 4-(2-fluorophenyl)-1,2,3,4-tetrahydro-6-methyl-2-oxopyrimidine-5-carboxylate (2.00 g, 7.2 mmol) was added in small portions to a stirred solution of a 60% nitric acid solution (12 mL) at 0° C. over 5 min. The resulting solution was warmed to room temperature (30 min) and then poured into ice and basified slowly with 6N NaOH. The product was extracted with CHCl₃ (3×50 mL), dried, and concentrated. The residue was purified by Biotage SP1 on packed silica gel column (7%-20% MeOH/CH₂Cl₂ gradient) to give ethyl 4-(2-fluorophenyl)-1,2-dihydro-6-methyl-2-oxopyrimidine-5-carboxylate as a green foam (1.5 g, 76%). Mass Spec. LCMS 277 (M+1).

Step iii: 4-(2-Fluorophenyl)-6-methyl-2-morpholin-4-yl-pyrimidine-5-carboxylic acid ethyl ester

Morpholine (0.5 mL) was added to a stirred solution of ethyl 4-(2-fluorophenyl)-1,2-dihydro-6-methyl-2-oxopyrimidine-5-carboxylate (0.75 g, 2.72 mmol), PyBroP (1.4 g, 3 mmol), and triethylamine (1 mL) in 1,4-dioxane (20 mL) at room temperature. The solution was stirred at room temperature for 3 h and diluted with EtOAc. The solution was washed with saturated NH₄Cl and saturated aqueous NaCl solution, and dried. The solvent was removed under reduced pressure, and the residue was purified by Biotage SP1 on packed silica gel column (5%-80% EtOAC/hexanes gradient) to give 4-(2-fluorophenyl)-6-methyl-2-morpholin-4-yl-pyrimidine-5-carboxylic acid ethyl ester as an oil (0.937 g, 64%). Mass Spec. LCMS 346 (M+1).

Step iv: 4-(2-Fluorophenyl)-6-methyl-2-morpholin-4-yl-pyrimidine-5-carboxylic acid

A mixture of 4-(2-fluorophenyl)-6-methyl-2-morpholin-4-yl-pyrimidine-5-carboxylic acid ethyl ester (0.6 g, 10.96 mmol), and solid NaOH (2 g, 50 mmol) in ethanol (5 mL) and water (1 mL) was refluxed for 1 h, then cooled to room temperature. The solvent was removed under reduced pressure, and the residue was acidified with a 6N HCl solution. Then, the product was extracted with EtOAC (3×25 mL) and the organic extracts were dried and concentrated to give 4-(2-fluorophenyl)-6-methyl-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (0.43 g, 78%) as white solid. Mass Spec. LCMS 318 (M+1).

Step v: 4-(2-Fluorophenyl)-6-methyl-2-morpholin-4-yl-pyrimidine-5-carboxylic acid benzyl-isopropyl-amide (Compound No. 338)

A solution of 2 M oxalyl chloride in CH₂Cl₂ (0.070 mL, 0.14 mmol) was added to a stirred solution of 4-(2-fluorophenyl)-6-methyl-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (0.03 g, 0.09 mmol) in CH₂Cl₂ (2 mL) and DMF (0.030 mL) at room temperature, and stirring continued for 15 min. A solution of N-benzylisopropylamine (0.013 g, 0.1 mmol) in CH₂Cl₂(1 mL) and diisopropylethylamine (0.044 mL, 0.25 mmol) were added and stirred for 24 hr. The solvent was removed under reduced pressure, and the residue was purified by Biotage SP1 on packed silica gel column (10%-80% EtOAc/Hexanes gradient) to give 4-(2-fluorophenyl)-6-methyl-2-morpholin-4-yl-pyrimidine-5-carboxylic acid benzyl-isopropyl-amide (0.016 g, 40%). Mass Spec. LCMS 449(M+1).

Following the procedures of Example 9, and making non-critical variations, the following compounds were prepared.

TABLE 6 Exemplary compounds prepared by the procedures of Example 9. Compound No. 49 83 173 186 245 251 253 259

Example 10 N-benzyl-4-(2-chlorophenyl)-N-Isopropyl-2-morpholinopyrimidine-5-carboxamide (Compound No. 194)

Synthesis of N-benzyl-4-(2-chlorophenyl)-N-isopropyl-2-morpholinopyrimidine-5-carboxamide: i. POCl₃, DMA ii. Pd₂(dba)₃, P(t-Bu)3, K₃PO₄, THF, 160° C., mW iii. Morpholine, 100° C. iv. A. NaOH, EtOH, 80° C., B. amine, BtSO₂Me, NEt₃, Dioxane, 160° C., mW

Step i. Ethyl 2,4-dichloropyrimidine-5-carboxylate

Under an N₂ atmosphere, a mixture of 5-carbethoxyuracil (1.0 g, 5.4 mmol) and POCl₃ (10 mL) was heated at reflux for 30 minutes. The solution was concentrated under reduced pressure to remove the excess of POCl₃, and the residue was poured into ice (20 g). CH₂Cl₂ (100 mL) was added, and the mixture was basified to pH 9 using saturated aqueous NaHCO₃ solution. The organic portion was dried over MgSO₄ and concentrated to obtain ethyl 2,4-dichloropyrimidine-5-carboxylate as a yellow oil (900 mg, 75%).

Step ii. Ethyl 2-chloro-4-(2-chlorophenyl)pyrimidine-5-carboxylate

In a microwave tube was added 1 eq. of ethyl 2,4-dichloropyrimidine-5-carboxylate (200 mg, 0.91 mmol), 0.5 eq. of 3-chlorophenyl boronic acid (67 mg), 0.1 eq. of Pd₂(dba)₃ (83 mg), 3 eq. of K₃PO₄ in 4 mL of Dioxane. To this solution was added 1 eq. of tri-(t-butyl)phosphine. The reaction was heated in the microwave to 160° C./300 W/for 1200 sec. The crude product was purified by prep HPLC. ES+=296.8.

Step iii. Ethyl 4-(2-cyanophenyl)-2-morpholinopyrimidine-5-carboxylate

A flask containing ethyl 2-chloro-4-(2-chlorophenyl)pyrimidine-5-carboxylate (50 mg) in 1 mL morpholine was heated to 100° C. for 12 h. The crude mixture was purified by prep HPLC. The ester was then hydrolyzed with NaOH in ethanol at reflux for 5 hrs. ES+=319.9, ES−=318.0.

Step iv. N-Benzyl-4-(2-chlorophenyl)-N-isopropyl-2-morpholinopyrimidine-5-carboxamide

In a microwave tube was added 1 eq. of 4-(2-chlorophenyl)-2-morpholino pyrimidine-5-carboxylic acid (80 mg), 1.1 eq. of isopropyl benzylamine (43 mL), 2.5 eq. of triethylamine (80 mL) and 1.2 eq. of BtSO₂Me in 4 mL of dioxane. The reaction mixture was heated to 160° C./300 W for 1200 sec. The crude product was purified by prep HPLC. ES+=451.0. NMR confirmed the structure.

Example 11

Following the procedures of Example 11, and making non-critical variations known in the art, the following compounds were prepared.

TABLE 7 Exemplary compounds prepared by the procedures of Example 11. Compound No. 16 17 46 89 121 123 139 168

A person skilled in the chemical arts can use the examples and schemes along with known synthetic methodologies to synthesize compounds of the present invention, including the compounds in Table 8 below.

TABLE 8 Physical data for exemplary compounds. Compound LC/MS LC/RT No. M + 1 min NMR 1 449.4 4 DMSO-d6: 8.49 (s, 1H), 7.59 (m, 1H), 7.52 (m, 1H), 7.35-7.42 (m, 2H), 7.11 (brm, 3H), 6.77 (brs, 2H), 3.78 (brm, 7H), 1.63 (brm, 2H), 1.53 (brm, 4H), 0.83 (brm, 6H) 2 505 4.1 DMSO-d6: 8.55 (s, 1H), 7.44 (m, 2H), 7.27 (d, 2H), 7.15 (m, 2H), 7.00 (d, 2H), 4.46 (brs, 2H), 4.12 (m, 4H), 2.64 (m, 4H), 1.95 (brm, 1H), 0.49 (brm, 4H). 3 491.5 4.5 DMSO-d6: 8.42 (s, 1H), 7.49 (br s, 2H), 7.41 (m, 1H), 7.28 (m, 1H), 7.22 (m, 1H), 7.12 (m, 1H), 6.74 (s, 1H), 6.38 (br s, 1H), 4.68 (br s, 1H), 3.67 (br s, 4H), 1.59 (br s, 2H), 1.43 (br s, 4H), 1.16 (s, 9H), 0.92 (br s, 6H). 4 490.3 4 DMSO-d6: 8.44 (s, 1H), 7.52 (m, 2H), 7.27 (m, 2H), 7.08 (m, 1H), 6.74 (m, 2H), 6.50 (m, 1H), 3.43-4.40 (m, 8H), 1.64 (m, 2H), 1.13 (m, 1H), 0.88 (m, 9H), 0.44 (m, 2H), 0.30 (m, 2H), 5 451 3.09 DMSO-d6: 8.51 (s, 1H), 7.49 (m, 2H), 7.30 (m, 2H), 6.94 (m, 1H), 6.34-6.62 (m, 3H), 4.30 (brs, 2H), 3.63-4.10 (m, 9H), 0.82 (brm, 6H). 6 534.3 3.7 DMSO-d6: 8.47 (s, 1H), 7.52 (m, 2H), 7.26 (m, 2H), 7.07 (m, 1H), 6.74 (m, 2H), 6.49 (m, 1H), 4.57 (m, 2H), 4.30 (m, 2H), 4.08 (q, 2H), 3.95 (m, 1H), 3.71 (s, 3H), 3.13 (m, 2H), 2.63 (m, 1H), 1.92 (m, 2H), 1.55 (2H), 1.18 (t, 3H), 0.92 (m, 6H) 7 489.5 3.8 DMSO-d6: 8.49 (s, 1H), 7.49 (m, 2H), 7.30 (m, 2H), 6.50-6.80 (brm, 3H), 4.49 (t, 2H), 4.35 (brs, 2H), 3.78 (t, 4H), 3.09 (t, 2H), 1.95 (brm, 1H), 1.63 (m, 2H), 1.53 (m, 4H), 0.49 (4H) 8 491.4 4.1 DMSO-d6: 8.41 (s, 1H), 7.53 (d, 1H, J = 8 Hz), 7.49 (t, 1H, J = 8 Hz), 7.43 (t, 1H, J = 8 Hz), 7.34 (d, 1H, J = 8 Hz), 7.14 (t, 1H, J = 8 Hz), 6.81 (d, 1H, J = 8 Hz), 6.32 (d, 1H, J = 7 Hz), 6.17 (s, 1H), 4.53 (br s, 1H), 3.69 (m, 4H), 3.63 (s, 3H), 1.62 (m, 4H), 1.46 (m, 4H), 1.39 (m, 4H), 1.22 (m, 2H). 9 465.2 3.4 DMSO-d6: 7.15-7.50 (m, 4H), 6.97 (t, 2H), 6.86 (m, 2H), 4.85 (d, 1H), 3.99 (d, 1H), 3.72 (m, 4H), 3.65 (m, 4H), 2.30 (s, 3H), 2.29 (s, 3H), 1.85 (m, 1H), 0.20-0.50 (m, 4H), 10 460.2 3.5 DMSO-d6: 7.15-7.47 (m, 4H), 7.01 (m, 2H), 6.78 (s, 1H), 6.54 (d, 1H) 4.79 (d, 1H), 4.02 (d, 1H), 3.73 (m, 4H), 3.65 (m, 4H), 2.30 (s, 3H), 2.22 (s, 3H), 1.90 (m, 1H), 0.20-0.46 (m, 4H), 11 392.2 3 12 503.5 4.2 DMSO-d6: 8.25 (s, 1H), 7.54 (m, 1H), 7.36 (m, 1H), 7.30 (m, 2H), 6.72 (d, 2H, J = 8 Hz), 6.61 (d, 2H, J = 6 Hz), 4.76 (m, 1H), 4.10 (m, 1H), 4.00 (m, 1H), 3.70 (s, 3H), 3.21 (m, 2H), 1.85 (m, 1H), 1.75 (m, 2H), 1.55-1.65 (m, 3H), 1.15-1.40 (m, 6H), 0.92 (s, 6H). 13 449.1 3.93 CD3OD: 7.45 (m, 2H), 7.13-7.25 (m, 5H), 6.90 (d, 1H), 4.75 (d, 1H), 4.25 (d, 1H), 3.85 (m, 4H), 3.73 (m, 4H), 2.41 (s, 3H), 3.0 (m, 1H), 1.05 (d, 3H), 0.61 (d, 3H) 14 508.5 2.4 DMSO-d6: 8.83 (d, 2H), 8.56 (s, 1H), 8.04 (d, 2H), 7.79 (d, 1H), 7.69 (brs, 1H), 7.25-7.50 (m, 6H), 4.61 (brs, 2H), 3.80 (m, 4H), 2.20 (brm, 1H), 1.64 (brm, 2H), 1.54 (brm, 4H), 0.54 (brm, 6H) 15 471.5 3.47 16 453.1 3.6 17 487.1 3 18 447 0.92 CD3OD: 8.73 (d, 2H), 8.71 (brs, 1H), 7.79 (m, 2H) 7.58 (m, 1H), 7.52 (m, 1H), 7.28 (m, 1H), 7.19 (m, 1H), 5.10 (brs, 2H), 4.85 (m, 2H), 3.40-3.65 (brm, 4H), 3.15 (brm, 2H), 2.98 (s, 3H), 2.41 (brm, 1H), 0.67 (m, 2H), 0.61 (m, 2H) 19 371 2.91 DMSO-d6: 1.33-1.46 (m, 6H), 1.70 (m, 2H), 3.66 (m, 4H), 3.77 (m, 4H), 4.03 (m, 1H) 7.17 (m, 1H), 7.26 (t, 1H), 7.46 (m, 1H), 7.53 (m, 1H), 7.90 (d, 1H), 8.50 (s, 1H) 20 462.2 3.8 DMSO-d6: 8.48 (s, 1H), 7.52 (m, 2H), 7.30 (m, 2H), 7.07 (m, 1H), 6.74 (m, 2H), 6.48 (m, 1H), 4.27 (m, 2H), 3.90 (m, 1H), 3.79 (m, 2H), 3.71 (s, 3H)), 1.50-165 (m, 6H), 0.91 (m, 6H). 21 465.5 3.3 CD3OD: 7.53 (m, 2H), 7.41 (m, 1H), 7.23 (m, 3H), 7.03 (m, 1H), 6.79 (m, 1H), 4.83 (m, 1H), 3.75 (m, 4H), 3.67 (s, 3H), 3.65 (m, 4H), 2.49 (s, 3H), 0.98 (d, 6H, J = 7 Hz). 22 511.2 4 DMSO-d6: 8.53 (s, 1H), 7.50 (m, 2H), 7.07-7.30 (m, 8H), 6.74 (m, 2H), 3.91-4.15 (m, 5H), 2.91 (m, 2H), 0.91 (m, 6H) 23 434.5 2.2 CD3OD: 8.44 (s, 1H), 7.58 (q, 1H, J = 8 Hz, 12 Hz), 7.37 (t, 1H, J = 7 Hz), 7.27 (t, 1H, J = 7 Hz), 7.21 (q, 2H, J = 11 Hz, 20 Hz), 7.15 (t, 2H, J = 8 Hz), 6.59 (d, 2H, J = 8 Hz), 4.87 (m, 1H), 3.52 (br s, 4H), 3.09 (br s, 4H), 2.92 (s, 3H), 1.05 (d, 6H, J = 7 Hz). 24 491 3.9 DMSO-d6: 8.51 (s, 1H), 7.53 (m, 1H), 7.55 (m, 1H)< 7.17-7.29 (m, 3H), 6.89 (m, 2H), 4.07 (m, 2H), 3.60-3.96 (9H), 1.25 (s, 9H), 0.90 (brm, 6H) 25 435.4 3.3 CD3OD: 7.55 (q, 1H, J = 7 Hz, 14 Hz), 7.18-7.46 (m, 6H), 7.13 (t, 2H, J = 7 Hz), 4.87 (m, 1H), 3.70 (m, 4H), 3.64 (m, 4H), 2.49 (s, 3H), 0.96 (d, 6H, J = 6 Hz). 26 447 3.68 DMSO-d6: 1.67 (brm, 2H), 1.70-2.10 (brm, 6H), 3.68 (brm, 4H), 3.78 (brm, 4H), 4.27 (m, 1H), 4.62 (brs, 2H), 6.99 (brm, 2H), 7.17-7.31 (m, 5H), 7.54 (m, 2H), 8.41 (s, 1H) 27 477.4 4 DMSO-d6: 8.39 (s, 1H), 7.52 (d, 1H, J = 7 Hz), 7.50 (t, 1H, J = 7 Hz), 7.42 (t, 1H, J = 11 Hz), 7.31 (d, 1H, J = 8 Hz), 7.19 (t, 1H, J = 8 Hz), 6.84 (d, 1H, J = 8 Hz), 6.34 (d, 1H, J = 8 Hz), 6.20 (s, 1H), 4.57 (m, 1H), 3.70 (t, 4H, J = 5 Hz), 3.68 (s, 3H), 1.92 (m, 2H), 1.66 (m, 2H), 1.59 (m, 2H), 1.48 (m, 5H), 1.39 (m, 1H). 28 463 1.82 CD3OD: 8.41 (s, 1H), 7.65 (t, 1H), 7.56 (m, 1H), 7.34 (m., 4H), 7.25 (t, 1H), 7.15 (d, 2H), 4.44 (s, 2H), 3.88 (m, 4H), 3.73 (m, 4H), 3.65 (m, 2H), 3.07 (m, 2H), 2.83 (s, 6H) 29 459.1 3.7 CD3OD: 8.38 (s, 1H), 7.51 (m, 2H), 7.18-7.30 (m, 5H), 7.04 (m, 2H),, 4.15 (s, 2H), 3.97 (m, 1H), 3.79 (m, 1H), 2.29 (m, 2H), 1.80 (m, 1H), 1.15-1.60 (8H), 1.01 (brm, 6H). 30 490.2 3.6 DMSO-d6: 8.44 (s, 1H), 7.50 (m, 2H), 6.90-7.15 (m, 4H), 6.60 (d, 1H), 4.53 (m, 4H), 4.22 (m, 4H), 3.15 (m, 2H), 2.65 (m, 4H), 1.80 (, 1H), 0.48 (m, 4H) 31 505.2 4 DMSO-d6: 7.23-7.55 (m, 4H), 7.13 (d, 2H), 6.76 (d, 2H), 4.56 (d, 1H), 4.16 (d, 1H), 3.63-3.73 (m, 8H), 2.34 (s, 3H), 1.25 (9H, m), 0.98 (d, 3H), 0.53 (d, 3H) 32 503.5 4.3 CD3OD: 7.17-7.52 (m, 6H), 6.86 (d, 1H), 6.81 (d, 1H), 4.68 (d, 1H), 4.23 (d, 1H), 3.81-3.87 (m, 5H), 2.39 (s, 1H)1.71 (m, 2H), 1.60 (m, 4H), 1.29 (d, 9H), 1.03 (d, 3H), 0.63 (d, 3H) 33 419.1 3.1 DMSO-d6: 8.58 (s, 1H), 8.45 (d, 1H), 7.57 (m, 1H), 7.49 (m, 1H), 7.09-7.30 (m, 6H), 5.30 (m, 1H), 3.77 (m, 4H), 3.66 (m, 4H), 2.86 (m, 1H), 2.78 (m, 1H), 2.35 (M, 1H), 1.76 (m, 1H) 34 503.5 4.2 DMSO-d6: 8.3 (s, 1H), 7.55 (m, 1H), 7.05, (m, 1H), 6.77 (d, 1H, J = 8 Hz), (m, 3H), 6.18 (m, 1H), 6.13 (br s, 1H), 4.76 (m, 1H), 4.08 (m, 3H), 3.63 (s, 3H), 3.20 (br d, 2H), 1.69 (m, 1H), 1.5-1.63 (m, 4H), 1.24-1.45 (M, 6H), 0.96 (br s, 6H). 35 491.5 3.5 DMSO-d6: 8.63 (s, 1H), 7.54 (m, 1H), 7.31 (m, 1H), 7.26 (m, 2H), 7.15 (m, 1H), 6.82 (d, 1H, J = 7 Hz), 6.34 (d, 1H, J = 8 Hz), 6.25 (s, 1H), 4.56 (br s, 1H), 3.86 (m, 4H), 3.79 (m, 2H), 3.62 (s, 3H), 3.32 (t, 2H, J = 11 Hz), 1.67 (m, 2H), 1.58 (m, 2H), 1.46 (m, 4H), 1.29 (m, 2H). 36 477.4 3.8 DMSO-d6: 8.49 (s, 1H), 7.49 (d, 1H), 7.44 (m, 1H), 7.31 (m, 2H), 6.84 (m, 2H), 6.76 (m, 2H), 4.35 (brs, 2H), 3.78 (m, 4H), 3.72 (s, 3H), 1.95 (m, 1H), 1.63 (m, 2H), 1.53 (m, 4H), 0.49 (m, 4H) 37 476.2 2.2 DMSO-d6 8.78 (s, 1H), 8.72 (d, 1H), 7.31-7.49 (m, 8H), 7.19 (t, 1H), 7.02 (t, 1H), 5.33 (m, 1H), 3.79 (t, 4H), 3.65 (t, 4H), 3.52 (m, 2H), 3.21 (m, 1H), 3.13 (m, 1H), 2.02 (m, 1H), 1.88 (m, 1H) 38 553.2 4.2 DMSO-d6: 8.44 (s, 1H), 7.51 (m, 2H), 7.07-7.30 (m, 8H),, 6.73 (m, 2H), 6.48 (m, 1H), 4.07-4.70 (m, 7H), 3.71 (s, 3H), 2.87 (m, 2H), 1.64-1.82 (m, 3H), 1.16 (m, 2H), 0.91 (m, 6H) 39 464 2.3 DMSO-d6 8.64 (s, 1H), 7.48 (m, 2H), 7.23 (m, 2H), 7.09 (m, 4H), 6.99 (m, 2H), 4.67 (d, 2H), 4.50 (brm, 2H), 3.50 (m, 2H), 3.31 (m, 2H), 3.10 (m, 2H), 2.84 (s, 3H), 2.00 (m, 1H), 0.48 (brm, 4H). 40 483 3.87 CD3OD: 8.45 (s, 1H), 8.17 (brs, 1H), 7.90 (m, 1H), 7.82 (m, 1H), 7.52 (m, 2H), 7.37 (m, m, 3H), 7.10 (brs, 1H), 6.80 (m, 2H), 5.09 (brs, 2H), 3.85 (m, 4H), 3.73 (m, 4H), 1.80 (brs, 1H), 0.60 (brm, 4H) 41 475.5 4.3 DMSO-d6: 8.34 (s, 1H), 7.45 (m, 1H), 7.25 (d, 3H, J = 5 Hz), 7.18 (d, 1H, J = 6 Hz), 7.06 (br s, 1H), 6.71 (s, 1H), 6.37 (br s, 1H), 4.75 (br s, 1H), 3.66 (br s, 4H), 1.59 (br s, 2H), 1.43 (br s, 4H), 1.12 (s, 9H), 0.98 (br s, 6H). 42 475.5 3.9 DMSO-d6: 8.34 (s, 1H), 7.54 (m, 1H), 7.34 (m, 1H), 7.27 (m, 2H), 7.12 (t, 1H, J = 8 Hz), 6.79 (d, 1H, J = 6 Hz), 6.34 (d, 1H, J = 7 Hz), 6.24 (s, 1H), 4.61 (m, 1H), 3.69 (m, 6H), 3.64 (s, 3H), 1.17, (br s, 2H), 1.59 (m, 2H), 1.44 (d, 6H, J = 18 Hz), 1.29 (m, 2H). 43 465.4 3.8 DMSO-d6: 8.33 (s, 1H), 7.55 (m, 1H), 7.49 (t, 1H, J = 7 Hz), 7.43 (t, 1H, J = 7 Hz), 7.35 (d, 1H, J = 7 Hz), 6.76 (m, 2H), 6.62 (d, 2H, J = 8 Hz), 4.72 (m, 1H), 3.71 (s, 3H), 3.66 (br s, 4H), 1.59 (br s, 2H), 1.45 (br s, 4H), 0.86 (d, 6H, J = 6 Hz). 44 477.2 3.4 DMSO-d6: 8.48 (s, 1H), 7.57 (m, 2H), 7.34 (m, 2H), 7.15 (m, 1H), 6.91 (m, 3H), 4.45 (brs, 2H), 3.78 (m, 4H), 3.75 (s, 1H), 3.67 (m, 4H), 3.60 (brm, 2H), 3.00 (brm, 2H), 1.30-1.80 (m, 4H) 45 434.2 2.8 CD3OD: 8.43 (s, 1H), 7.53 (m, 2H), 7.03-7.30 (m, 7H), 7.05 (m, 2H), 4.50 (m, 2H), 4.15 (d, 2H), 3.97 (m, 1H), 3.70 (m, 3H), 2.05 (m, 2H), 1.01 (brm, 6H). 46 495.1 3.5 NMR 1H (DMSO-d6): 8.4 (s, 1H), 8.3 (s, 1H), 7.7 (m, 2H), 7.4 (m, 2H), 7.0-7.3 (m, 10H), 3.8 (s, 4H), 3.7 (s, 4H), 3.1 (m, 2H), 2.5 (m, 2H), 1.7 (m, 2H). 47 491 3.9 DMSO-d6: 8.51 (s, 1H), 7.10-7.60 (m, 7H), 6.95 (d, 2H), 3.95-4.25 (6H), 3.35 (m, 1H), 2.65 (m, 4H), 0.90-1.60 (m, 10H) 48 467 3.6 DMSO-d6: 8.56 (s, 1H), 7.47 (t, 2H), 7.19 (m, 2H), 7.06-7.12 (d, 4H), 4.48 (brs, 2H), 4.12 (m, 4H), 2.63 (m, 4H), 2.02 (brm, 1H), 0.49 (brm, 4H). 49 492.3 3.6 DMSO-d6: 6.75-7.50 (m, 9H), 4.47 (d, 1H), 4.33 (d, 1H), 3.63-3.69 (m, 8H), 3.45 (m, 1H), 3.02 (s, 3H), 2.37 (s, 3H), 1.05 (m, 2H), 0.50 (t, 3H) 50 502.5 3.1 DMSO-d6: 8.46 (s, 1H), 7.53 (brm, 2H), 7.28 (brm, 2H)_, 6.84 (brm, 2H), 6.38 (brm, 2H), 4.14 (brm, 9H), 3.18 (brm, 4H), 1.93 (brm, 4H), 1.64 (brm, 2H), 1.53 (m, 4H), 0.88 (brm, 6H) 51 484.2 3.4 52 433.1 3.5 CDCl3: 8.27 (brs, 1H), 7.29 (q, 1H), 7.11 (brs, 1H), 7.01 (t, 1H), 6.92 (m, 3H), 6.82 (d, 2H), 6.64 (brs, 1H), 4.71 (brm, 2H), 3.70-3.90 (m, 8H), 2.33 (m, 1H), 2.11 (m, 1H), 1.27 (m, 1H), 1.07 (d, 3H) 53 475 3.4 CD3OD: 88.45 (s, 1H), 7.46 (m, 1H), 7.39 (m, 1H), 7.10 (m, 1H), 7.00 (m, 2H), 6.89 (m, 1H), 6.60 (d, 1H), 4.53 (m, 4H), 3.87 (t, 4H)< 3.74 (t, 4H), 3.15 (t, 2H), 1.84 (brm, 1H), 0.47-0.55 (brm, 4H) 54 498.5 4 DMSO-d6: 8.42 (s, 1H), 7.66 (m, 1H), 7.60 (m, 1H), 7.35 (m, 1H), 7.29 (m, 2H), 7.23 (m, 1H), 6.93 (m, 1H), 6.83 (br s, 1H), 4.74 (br s, 1H), 4.24 (m, 2H), 1.85 (m, 1H), 1.54-1.69 (m, 5H), 1.45 (m, 1H), 1.33 (m, 4H), 1.24 (m, 3H), 0.95 (dd, 6H, J = 6 Hz, 20 Hz). 55 479.4 3.9 DMSO-d6: 8.47 (m, 1H), 7.35-7.56 (m, 4H), 7.00 (m, 1′H), 6.64-6.75 (m, 2H), 6.25 (m, 1H), 3.77 (m, 7H), 3.69 (s, 3H), 1.63 (m, 2H), 1.64 (m, 2H), 1.53 (m, 4H), 0.84 (brm, 6H) 56 463 3.3 DMSO-d6: 8.58 (s, 1H), 7.46 (m, 2H), 7.17 (m, 3H), 6.79 (dd, 1H), 6.75 (m, 1H), 6.63 (t, 1H), 4.48 (brs, 2H), 3.78 (m, 4H), 3.72 (s, 3H), 3.67 (m, 4H), 2.15 (brm, 1H), 0.50 (m, 4H) 57 502.2 3.3 DMSO-d6: 8.44 (s, 1H), 7.55 (t, 1H), 7.45 (m, 1H), 7.37 (t, 2H), 7.21-7.29 (m, 5H), 3.78 (t, 4H), 3.67 (t, 4H), 3.00-3.35 (brm, 8H), 2.19 (m, 2H), 0.73 (t, 3H) 58 463.4 3.8 DMSO-d6: 8.48 (s, 1H), 7.95 (d, 1H, J = 8 Hz), 7.67 (m, 1H), 7.49 (m, 1H), 7.36 (m, 2H), 7.17 (m, 1H), 6.58 (m, 1H), 6.28 (m, 1H), 3.66 (s, 3H), 3.57 (br s, 4H), 2.74 (m, 1H), 1.60 (m, 2H), 1.49 (m, 4H), 0.85 (m, 1H), 0.65 (m, 1H), 0.51 (m, 1H), 0.36 (m, 1H). 59 507.1 4.2 DMSO-d6: 8.50 (s, 1H), 7.53 (m, 1H), 7.45 (m, 1H), 7.18-7.26 (m, 3H), 6.90 (m, 2H), 4.10 (m, 6H), 3.85 (m, 1H), 2.63 (m, 4H), 1.25 (s, 9H), 0.91 (brm, 6H) 60 510 2.1 CD3OD: 8.67 (d, 2H), 8.52 (s, 1H), 8.36 (d, 2H), 7.90 (m, 2H), 7.57 (t, 1H), 7.46 (m, 2H), 7.25 (m, 1H), 7.10 (m, 1H), 6.80 (m, 1H), 4.73 (m, 1H), 3.88 (m, 4H), 3.74 (m, 4H), 2.02 (m, 1H), 0.62 (m, 4H) 61 535.2 3.7 DMSO-d6: 8.41 (s, 1H), 7.06-8.21 (m, 11 H), 6.73 (m, 2H), 6.40 (m, 1H), 5.01 (m, 2H), 4.35 (m, 2H), 3.95 (m, 1H), 3.70 (s, 3H), 0.91 (m, 6H) 62 467.4 3.6 DMF-d7: 8.42 (s, 1H), 7.55 (m, 1H), 7.35 (br s, 1H), 7.28 (m, 2H), 7.10 (m, 1H), 6.79 (d, 1H, J = 9 Hz), 6.29 (br s, 1H), 6.19 (br s, 1H), 4.78 (br s, 1H), 4.00 (br s, 4H), 3.64 (s, 3H), 2.54 (br s, 4H), 0.96 (br s, 6H). 63 454.2 3.6 64 475 3.88 DMSO-d6: 0.9-1.65 (brm, 10H), 1.51 (brm, 4H), 3.28 (m, 1H), 3.68 (brm, 4H), 3.77 (brm, 4H), 4.03 (brm, 1H), 6.93 (brd, 2H), 7.15 (brm, 3H), 7.29 (m, 2H), 7.45 (m, 1H), 7.55 (m, 1H), 8.52 (s, 1H) 65 515.5 4.4 DMSO-d6: 8.28 (s, 1H), 7.52 (m, 1H), 7.36, (m, 1H), 7.26 (m, 2H), 7.17 (t, 1H, J = 8 Hz), 6.77 (d, 1H, J = 8 Hz), 6.80 (d, 1H, J = 8 Hz), 6.32 (d, 1H, J = 7 Hz), 6.26 (s, 1H), 4.66 (m, 1H), 4.08 (m, 3H), 3.66 (s, 3H), 3.23 (m, 2H), 1.86 (m, 2H), 1.72 (m, 1H), 1.69 (m, 4H), 1.43 (m, 4H), 1.34 (m, 6H). 66 435.5 3.2 DMSO-d6: 9.44 (s, 1H), 8.28 (s, 1H), 7.54 (m, 1H), 7.37 (m, 1H), 7.26 (m, 2H), 6.98 (t, 1H, J = 7 Hz), 6.61 (d, 1H, J = 8 Hz), 6.16 (m, 2H), 4.70 (br s, 1H), 3.69 (br s, 4H), 1.58 (m, 2H), 1.47 (m, 4H), 0.95 (d, 6H, J = 6 Hz). 67 479.4 3.1 DMSO-d6: 8.39 (s, 1H), 7.54 (m, 1H), 7.37 (m, 1H), 7.27 (m, 2H), 6.65 (d, 1H, J = 8 Hz), 6.25 (d, 1H, J = 8 Hz), 6.02 (s, 1H), 4.73 (m, 1H), 4.19 (s, 4H), 3.66 (br s, 4H), 3.61 (br s, 4H), 0.92 (d, 6H, J = 6 Hz). 68 545.6 4.1 DMSO-d6: 8.30 (s, 1H), 7.55 (m, 1H), 7.30 (m, 1H), 7.26 (m, 2H), 7.15 (m, 1H), 7.10 (m, 1H), 6.80 (d, 1H, J = 8 Hz), 6.23 (s, 1H), 4.70 (br s, 1H), 4.13 (m, 2H), 3.80 (m, 2H), 3.65 (s, 3H), 3.30 (m, 2H), 1.85 (m, 1H), 1.69 (m, 2H), 1.50-1.63 (m, 4H), 1.22-1.44 (m, 11H). 69 462.2 3.6 70 463.4 3.6 DMSO-d6: 8.34 (s, 1H), 7.54 (m, 1H), 7.36 (br s, 1H), 7.28 (m, 2H), 6.71 (d, 1H, J = 6 Hz), 6.18 (m, 2H), 6.00 (s, 2H), 4.73 (m, 1H), 3.69 (br s, 4H), 1.60 (br s, 2H), 1.47 (br s, 4H), 0.93 (d, 6H, J = 6 Hz). 71 463.1 3.4 DMSO-d6: 8.46 (2 × s, 1H), 7.01-7.67 (m, 8H), 5.74 &6.02 (2 × s, 1H), 4.16 (brs, 1H), 3.86-3.90 (m, 7H), 3.75 (m, 4H), 3.44 (m, 1H), 2.44 (m, 1H), 72 436.2 2.6 73 484 2.94 74 465 3.48 CDCl3: 8.37&8.18 (2 × s, 1H), 7.00-7.60 (m, 4H), 6.51-6.72 (m, 3H), 4.36 (brs, 2H), 3.66-4.02 (m, 9H), 3.69 (s, 3H), 0.88 (brm, 6H) 75 446 3.17 CD3OD: 8.37 (s, 1H), 7.00-7.70 (m, 9H),, 4.46 (brs, 2H), 3.86 (m, 4H), 3.73 (m, 4H), 3.58 (m, 2H), 2.56 (t, 2H). 76 471.4 3.5 DMSO-d6: 8.35 (s, 1H), 7.87 (d, 1H, J = 8 Hz), 7.81 (d, 1H, J = 8 Hz), 7.76 (d, 1H, J = 8 Hz), 7.61 (m, 1H), 7.55 (t, 1H, J = 8 Hz), 7.49 (t, 1H, J = 8 Hz), 7.35 (m, 3H), 7.23 (t, 1H, J = 8 Hz), 6.24 (d, 1H, J = 7 Hz), 4.82 (m, 1H), 3.49 (s, 4H), 3.34 (s, 4H), 1.13 (d, 3H, J = 6 Hz), 0.77 (d, 3H, J = 6 Hz). 77 473.5 3.6 DMSO-d6: 8.48 (m, 1H), 7.45 (m, 2H), 7.30 (m, 2H), 6.89 (s, 1H), 6.79 (m, 1H), 6.61 (d, 1H), 4.51 (t, 2H), 4.40 (brs, 2H), 3.80 (t, 2H), 3.12 (t, 2H), 1.95 (brm, 1H), 1.63 (m, 2H), 1.54 (m, 4H), 0.47 (brm, 4H) 78 480.2 4 CD3OD: 8.48 (s, 1H), 7.53 (m, 2H), 7.00-7.45 (m, 1H), 4.96 (brs, 4H), 4.10 (s, 2H), 3.97 (m, 1H), 2.94 (m, 2H), 1.02 (brm, 6H) 79 343 2.4 DMSO-d6: 0.34 (m, 2H), 0.59 (m, 2H), 2.61 (m, 1H), 3.65 (m, 4H), 3.78 (m, 4H), 7.19 (m, 1H), 7.29 (t, 1H), 7.48 (m, 1H), 7.53 (m, 1H), 8.11 (d, 1H), 8.49 (s, 1H) 80 463 3.8 DMSO-d6: 8.40 (s, 1H), 7.55 (m, 2H), 7.15-7.31 (m, 5H), 7.00 (m, 2H), 4.63 (brS, 2H), 4.27 (m, 1H), 4.13 (m, 4H), 2.66 (m, 4H), 1.33-2.15 (brm, 6H) 81 495 4.06 CD3OD: 8.50 (s, 1H), 7.50 (m, 2H), 7.05-7.25 (m, 9H), 4.10-4.25 (m, 8H), 4.60 (m, 1H), 3.17 (s, 3H), 2.60-2.67 (m, 4H), 1.30-1.60 (m, 2H), 0.64 (m, 3H) 82 435.4 3.9 DMSO-d6: 8.37 (s, 1H), 7.53 (m, 2H), 7.43 (t, 1H, J = 7 Hz), 7.33 (d, 1H, J = 7 Hz), 7.24 (s, 3H), 6.70 (br s, 2H), 4.65 (br s, 1H), 3.67 (br s, 4H), 1.58 (br s, 2H), 1.45 (br s, 4H), 0.88 (d, 6H, J = 6 Hz). 83 450.2 3.6 CD3OD: 8.41 (s, 1H), 7.57 (m, 2H), 7.22 (m, 5H), 7.05 (m, 2H), 4.09 (m, 2H), 3.55-4.15 (m, 7H), 3.57 (s, 3H), 1.20 (t, 2H), 1.01 (brm, 6H). 84 435.4 3.2 DMSO-d6: 8.60 (br s, 1H), 7.45 (m, 2H), 7.18 (m, 2H), 6.94 (m, 2H), 6.69 (m, 2H), 4.61 (br s, 1H), 4.05 (m, 2H), 3.67-3.92 (br m, 8H), 1.00 (br s, 3H). 85 517 3.8 DMSO-d6: 8.60 (s, 1H), 7.62 (d, 2H), 7.46 (m, 2H), 7.30 (d, 2H), 7.20 (m, 2H), 4.59 (brs, 2H), 4.12 (m, 4H), 2.64 (m, 4H), 2.15 (brm, 1H), 0.51 (brm, 4H). 86 491.5 3.6 DMSO-d6: 8.40 (s, 1H), 7.55 (m, 1H), 7.37 (br s, 1H), 7.30 (d, 2H, J = 6 Hz), 7.11 (m, 1H), 6.79 (d, 1H, J = 7 Hz), 6.32 (m, 1H), 6.21 (br s, 1H), 4.37 (m, 1H), 3.65 (s, 3H), 3.58 (br d, 8H, J = 16 Hz), 1.67 (m, 4H), 1.49 (d, 1H, J = 11 Hz), 1.24 (m, 2H), 0.97 (m, 2H), 0.86 (m, 1H). 87 464.5 2.2 CD3OD: 8.47 (s, 1H), 7.55 (m, 1H), 7.39 (m, 1H), 7.27 (m, 1H), 7.21 (m, 1H), 7.05 (m, 1H), 6.77 (m, 1H), 6.22 (m, 1H), 6.10 (m, 1H), 4.85 (m, 1H), 3.66 (s, 3H), 3.50 (br s, 4H), 3.09 (br s, 4H), 2.92 (s, 3H), 1.06 (d, 6H, J = 7 Hz). 88 421 3.52 CD3OD: 8.34 (s, 1H), 7.54 (m, 1H), 7.10-7.40 (m, 6H), 6.60 (m, 2H), 4.90 (brm, 1H), 3.74 (m, 4H), 3.67 (m, 4H), 1.06 (brm, 4H) 89 477.2 3.1 90 431.5 3.7 CD3OD:: 8.43 (s, 1H), 7.49 (m, 1H), 7.39 (m, 1H), 7.00-7.30 (m, 7H), 4.59 (m, 2H), 3.88 (m, 4H), 1.91 (m, 1H), 1.72 (m, 2H), 1.63 (m, 4H), 0.52 (m, 4H) 91 445.2 3.3 DMSO-d6: 8.50 (s, 1H), 7.20-7.70 (m, 9H), 5.90&6.15 (2 × s, 1H), 4.07 (brs, 1H), 3.68-3.80 (m, 11H), 2.35 (m, 2H) 92 487.5 4.4 CD3OD: 8.38 (s, 1H), 7.05-7.70 (brm, 9H), 4.4 (m, 4H), 3.97 (m, 1H), 3.40 (m, 2H), 1.35-1.95 (m, 12H), 1.02 (m, 6H) 93 419.4 3.7 DMSO-d6: 8.91 (s, 1H), 8.39 (d, 1H, J = 2 Hz), 7.71 (m, 1H), 7.55 (m, 2H), 7.42 (m, 1H), 7.33 (m, 3H), 7.21 (br s, 1H), 4.06 (m, 1H), 3.89 (m, 2H), 3.67 (m, 2H), 1.59 (m, 4H), 1.45 (m, 2H), 0.94 (br s, 6H). 94 477.5 3.7 DMSO-d6: 8.44 (s, 1H), 7.51 (m, 2H), 7.26 (m, 2H), 6.69 (m, 1H), 6.61 (s, 1H), 6.50 (m, 1H), 5.96 (s, 2H), 4.59 (m, 2H), 3.79-4.00 (m, 7H), 1.63 (m, 2H), 1.54 (m, 4H), 0.90 (m, 6H) 95 527.5 4.2 CD3OD: 8.39 (s, 1H), 7.46 (m2H), 6.85-7.25 (m, 4H), 6.60 (d, 1H), 4.53 (t, 2H), 4.47 (m, 4H), 3.40 (m, 2H), 3.15 (t, 2H), 1.97 (m, 1H), 1.30-1.85 (m12H), 0.50 (m, 4H) 96 445.2 3.4 CD3OD: 8.48 (s, 1H), 7.51 (m, 2H), 6.99-7.35 (m, 7H), 4.50 (m, 1H), 4.06 (s, 2H), 3.60-3.95 (m, 6H), 2.85 (t, 2H), 1.25 (t, 3H), 1.02 (brm, 6H) 97 419.1 3.1 DMSO-d6: 8.54 (s, 1H), 8.39 (d, 1H), 7.55 (m, 1H) 7.50 (m, 1H), 7.06-7.30 (m, 7H), 3.78 (t, 4H), 3.66 (m, 4H), 2.80 (m, 1H), 1.88 (m, 1H), 1.13 (m, 2H), 98 451 3.7 DMSO-d6: 8.52 (s, 1H), 6.95-7.65 (m, 9H), 4.00-4.25 (m, 6H), 3.90 (m, 1H), 2.5 (m, 4H), 0.91 (brS, 6H) 99 484 2.64 CD3OD: 9.11 (s, 1H), 8.87 (m, 2H), 8.56 (s, 1H), 8.25 (m, 2H), 8.16 (m, 1H), 7.98 (m, 1H), 7.47 (m, 1H), 7.20 (m, 1H), 6.98 (m, 1H), 6.65 (m, 1H), 4.90 (brs, 2H), 3.88 (t, 4H), 3.74 (t, 4H), 2.22 (brm, 1H), 0.72 (m, 2H), 0.64 (m, 2H) 100 433 3.41 DMSO-d6: 0.48 (brs, 4H), 2.08 (brs, 1H), 3.67 (m, 1H), 3.77 (m, 4H), 4.51 (brs, 2H), 7.06 (d, 2H), 7.21-7.26 (m, 5H), 7.48 (m, 2H), 8.58 (s, 1H) 101 460.5 3.7 DMSO-d6: 8.50 (s, 1H), 7.70 (d, 1H, J = 8 Hz), 7.54 (d, 2H, J = 4 Hz), 7.45 (m, 2H), 7.29 (d, 1H, J = 8 Hz), 7.04 (d, 1H, J = 8 Hz), 6.79 (br s, 1H), 4.63 (br s, 1H), 3.70 (br s, 4H), 1.59 (m, 2H), 1.46 (m, 4H), 0.90 (d, 6H, J = 6 Hz). 102 454.2 2.17 103 481.2 3.6 CD3OD: 8.45 (s, 1H), 7.50 (m, 2H), 7.25 (m, 3H), 7.09 (m, 1H), 6.73 (m, 2H), 6.50 (m, 1H), 3.50-4.10 (m, 9H), 3.75 (s, 3H), 3.25 (brm, 3H), 1.23 (brm, 3H), 0.91 (brm, 6H) 104 463.5 3.7 DMF-d7: 7.57 (m, 1H), 7.35 (m, 1H), 7.26 (m, 2H), 7.05 (t, 1H, J = 8 Hz), 6.79 (m, 1H), 6.00 (br s, 1H), 5.75 (br s, 1H), 4.75 (m, 1H), 3.83 (br s, 2H), 3.62 (s, 3H), 3.61 (br s, 2H), 2.40 (s, 3H), 1.56 (m, 2H), 1.42 (m, 4H), 0.87 (dd, 6H, J = 7 Hz, 12 Hz). 105 473.5 4.3 CDCl3: 8.27 (s, 1H), 7.46 (m, 2H), 7.17 (m, 5H), 6.65 (br s, 2H), 4.92 (m, 1H), 4.28 (br d, 1H, J = 8 Hz), 4.20 (br d, 1H, J = 8 Hz), 3.31 (m, 2H), 1.98 (s, 1H), 1.87 (m, 1H), 1.74 (m, 2H), 1.56 (m, 2H), 1.49 (m, 1H), 1.28 (m, 4H), 1.36 (m, 4H), 1.04 (br s, 6H). 106 480.2 2.6 107 419 3.3 DMSO-d6: 8.50 (s, 1H), 6.95-7.60 (m, 8H), 4.57 (brs, 1H), 4.42 (brs, 1H), 3.80 (m, 4H), 3.68 (m, 5H), 3.42 (brm, 1H), 2.50-2.71 (brm, 2H) 108 449.4 3.7 DMSO-d6: 8.28 (s, 1H), 7.55 (m, 1H), 7.37 (m, 1H), 7.30 (m, 2H), 6.74 (d, 2H, J = 8 Hz), 6.63 (d, 2H, J = 8 Hz), 4.76 (m, 1H), 3.70 (s, 3H), 3.67 (br s, 4H), 1.59 (m, 2H), 1.46 (m, 4H), 0.91 (d, 6H, J = 6 Hz). 109 449 3.6 DMSO-d6: 8.56 (s, 1H), 7.48 (t, 2H), 7.21-7.26 (m, 5H), 7.06 (d, 2H), 4.50 (brS, 2H), 4.12 (m, 4H), 2.64 (m, 4H), 2.00 (m, 1H), 0.48 (m, 4H) 110 451 3.3 DMSO-d6: 8.61 (s, 1H), 7.47 (m, 2H), 7.29 (m, 1H), 7.20 (m, 2H), 7.06 (m, 1H), 6.91 (t, 2H), 4.51 (brs, 2H), 3.78 (m, 4H), 3.67 (m, 4H), 2.15 (brm, 1H), 0.51 (m, 4H) 111 464.5 2.5 DMSO-d6: 8.40 (s, 1H), 7.54 (m, 1H), 7.38 (m, 1H), 7.26 (m, 2H), 6.98 (m, 1H), 6.55 (d, 1H, J = 7 Hz), 6.04 (s, 2H), 4.73 (br s, 1H), 3.64 (br s, 4H), 3.60 (br s, 4H), 2.78 (s, 6H), 0.97 (d, 6H, J = 6 Hz). 112 469.5 3.9 DMSO-d6: 8.27 (s, 1H), 7.86 (d, 1H, J = 8 Hz), 7.80 (d, 1H, J = 8 Hz), 7.74 (d, 1H, J = 8 Hz), 7.62 (m, 1H), 7.54 (t, 1H, J = 7 Hz), 7.48 (t, 1H, J = 7 Hz), 7.33 (m, 3H), 7.21 (t, 1H, J = 7 Hz), 6.24 (d, 1H, J = 8 Hz), 4.80 (m, 1H), 3.46 (br s, 4H), 1.50 (m, 2H), 1.32 (br s, 4H), 1.13 (d, 3H, J = 6 Hz), 0.77 (d, 3H, J = 6 Hz). 113 479 3.63 CD3OD: 0.64 (t, 3H), 1.55 (m, 2H), 3.15 (s, 3H), 3.07-3.80 (m, 7H), 3.87 (m, 4H), 4.20 (m, 2H), 7.06-7.53 (m, 9H), 8.48 (s, 1H) 114 562.5 2.9 CD3OD: 8.86 (d, 2H), 8.44 (s, 1H), 8.37 (d, 2H), 7.89 (m, 2H), 7.57 (t, 1H), 7.55 (m, 2H), 7.30 (m, 1H), 7.15 (m, 1H), 6.80 (m, 1H), 4.70 (m, 2H),, 4.40 (m, 4H), 3.40 (m, 2H), 3.15 (t, 2H), 1.95 (m, 1H), 1.30-1.85 (m12H), 0.63 (m, 2H), 0.56 (m, 2H) 115 505.5 4.2 DMSO-d6: 8.41 (s, 1H), 7.52 (m, 2H), 7.44 (t, 1H, J = 7 Hz), 7.34 (d, 1H, J = 7 Hz), 7.13 (m, 1H), 6.81 (d, 1H, J = 7 Hz), 6.31 (d, 1H, J = 7 Hz), 6.15 (s, 1H), 4.38 (br s, 1H), 3.67 (s, 3H), 3.34 (br s, 4H), 1.55-1.63 (m, 5H), 1.45 (br s, 5H), 1.22 (m, 3H), 0.84-0.93 (m, 3H). 116 461.4 3.8 DMSO-d6: 8.31 (s, 1H), 7.52 (m, 1H), 7.39 (t, 1H, J = 7 Hz), 7.27 (m, 2H), 7.17, (t, 1H, J = 6 Hz), 6.82 (d, 1H, J = 8 Hz), 6.36 (d, 1H, J = 8 Hz), 6.28 (s, 1H), 4.66 (m, 1H), 3.71 (t, 4H, J = 6 Hz), 3.67 (s, 3H), 1.98 (m, 2H), 1.68 (m, 2H), 1.59 (m, 2H), 1.49 (m, 6H). 117 433.5 3.8 DMSO-d6: 8.46 (s, 1H), 7.55 (m, 1H), 7.54 (m, 1H), 7.15-7.30 (m, 5H), 6.95 (m, 2H), 3.70-4.10 (m, 7H), 1.64 (brm, 2H), 1.54 (brm, 6H), 0.9 (brm, 6H) 118 487 3.91 CD3OD: 8.37 (s, 1H), 7.47-7.53 (m, 3H), 7.18-7.27 (m, 6H), 7.04 (m, 2H), 6.96 (m, 2H), 4.12 (s, 2H), 3.95 (m, 1H), 3.68 (m, 2H), 2.92 (m, 2H), 1.02 (m, 6H). 119 505.5 4.5 CD3OD:: 8.48 (s, 1H), 7.57 (d, 1H), 7.50 (t, 1H), 7.49 (m, 1H), 7.39 (m, 1H), 7.00-7.30 (m, 7H), 7.35 (m, 2H), 7.11 (m, 2H), 6.72 (m, 2H), 3.95 (m, 1H), 3.78 (m, 6H), 1.91 (m, 1H), 1.63 (m, 2H), 1.53 (m, 4H), 1.24 (s, 9H), 0.83 (m, 4H) 120 531.5 4.2 CD3OD: 8.36 (s, 1H), 7.49 (m, 2H), 7.24 (m, 1H), 7.15 (m, 1H), 6.56-6.70 (m, 3H), 5.90 (s, 2H), 4.4 (m, 4H), 3.95 (m, 1H), 3.40 (m, 2H), 1.35-1.95 (m, 12H), 1.02 (m, 6H) 121 497.1 3.4 NMR 1H (DMSO-d6): 8.6 (s, 1H), 8.4 (s, 1H), 7.7 (m, 2H), 7.4 (m, 2H), 7.2 (m, 3H), 7.0 (m, 2H), 6.9 (m, 5H), 4.0 (t, 2H), 3.8 (m, 4H), 3.7 (m, 4H), 3.5 (m, 2H). 122 489.5 4.3 DMSO-d6: 8.45 (m, 1H), 7.60 (m, 1H), 7.54 (m, 1H), 7.54 (m, 1H), 7.17-7.30 (m, 4H), 6.90 (m, 2H), 3.70-4.10 (m, 7H), 1.63 (brm, 2H), 1.54 (brm, 6H), 0.91 (brm, 6H) 123 509 4.08 NMR 1H (CDCl3): “Show rotameres” 8.3 (s, 1H), 7.8 (d, 2H), 6.9-7.4 (m, 12H), 4.7 (m, 2H), 4.4 (m, 1H), 3.7-4.0 (m, 8H), 1.0-1.1 (2 × s, 4H), 0.6 (s, 2H). 124 501 3.5 DMSO-d6: 8.62 (s, 1H), 7.62 (m, 2H), 7.46 (brm, 2H), 7.30 (d, 2H), 7.20 (m, 2H), 4.59 (brs, 2H), 3.78 (m, 4H),, 3.67 (m, 4H), 2.06 (brm, 1H), 0.52 (brm, 4H) 125 444.5 3.6 DMSO-d6: 8.45 (s, 1H), 7.67 (d, 1H, J = 7 Hz), 7.58 (m, 1H), 7.38 (m, 1H), 7.29 (m, 3H), 7.01 (m, 1H), 6.82 (br s, 1H), 4.70 (br s, 1H), 3.70 (br s, 4H), 1.60 (m, 2H), 1.46 (m, 4H), 0.95 (d, 6H, J = 6 Hz). 126 514 2.5 DMSO-d6 8.69 (s, 1H), 7.62 (d, 2H), 7.48 (m, 2H), 7.29 (d, 2H), 7.23 (m, 2H), 4.77 (d, 2H), 4.60 (brm, 2H), 3.53 (m, 2H), 3.32 (m, 2H), 3.30 (m, 2H), 2.84 (s, 3H), 2.10 (m, 1H), 0.51 (brm, 4H). 127 489.5 4 DMSO-d6: 8.34 (s, 1H), 7.54 (m, 1H), 7.36 (br s, 1H), 7.28 (m, 2H), 7.10 (m, 1H), 6.79 (d, 1H, J = 8 Hz), 6.31 (m, 1H), 6.20 (s, 1H), 4.31 (br s, 1H), 3.68 (br s, 4H), 3.65 (s, 3H), 1.66 (m, 2H), 1.59 (m, 2H), 1.46 (m, 6H), 1.24 (m, 2H), 0.97 (m, 2H), 0.85 (m, 2H). 128 451 3.3 DMSO-d6: 8.57 (s, 1H), 7.47 (m, 2H), DMSO-d6: 7.21 (m, 2H), 7.11 (m, 4H), 4.48 (brs, 2H), 3.77 (m, 4H),, 3.67 (m, 4H), 2.05 (brm, 1H), 0.49 (brm, 4H) 129 446 2.2 DMSO-d6 0.5 (brm, 4H), 0.85 (brm, 1H), 2.95 (s, 3H), 3.15-3.65 (brm, 6H), 4.60 (brm, 2H), 5.02 (brs, 2H), 6.95-7.45 (m, 9H), 8.56 (s, 1H) 130 467 3.8 CD3OD: 8.51 (s, 1H), 7.58 (m, 2H), 7.06-7.40 (m, 9H), 7.06 (m, 2H), 4.96 (brs, 4H), 4.15 (s, 2H), 4.00 (m, 1H), 1.03 (brm, 6H) 131 481 3.94 CD3OD: 8.45 &8.00 (2 × s, 1H), 7.11-7.65 (m, 5H), 6.52-6.80 (m, 3H), 3.95-4.25 (m, 7H), 3.75 (s, 3H), 2.65 (m, 4H), 1.02 (brm, 6H). 132 457 3.22 133 449 3.94 CDCl3: 8.26 (s, 1H), 7.41 (m, 2H), 7.17 (t, 1H, J = 8 Hz), 7.07 (m, 2H), 6.70 (d, 1H, J = 7 Hz), 6.29 (br s, 1H), 6.14 (br s, 1H), 5.90 (br m, 1H), 3.73 (br S, 4H), 3.66 (s, 3H), 1.62 (br s, 2H), 0.85 (d, 6H, J = 7 Hz). 134 497.1 3.8 DMSO-d6: 8.56 (s, 1H), 7.20-7.60 (8H), 7.08 (m, 1H), 6.73 (m, 2H), 6.50 (m, 1H), 4.92 (brm, 2H), 4.87 (brm, 2H), 4.11 (brs, 2H), 3.92m, 1H), (s, 3H), 0.92 (brm, 6H) 135 505.1 3.7 CD3OD: 8.45 (s, 1H), 8.15 (d, 1H), 7.87 (d, 1H), 7.79 (d, 1H), 7.49 (m, 5H), 7.43 (t, 1H), 7.18 (m, 5H), 7.03 (m, 2H), 5.12 (s, 2H), 4.10 (s, 2H), 3.97 (m, 1H), 1.02 (brm, 6H). 136 459.5 4 DMSO-d6: 8.43 (s, 1H), 7.57 (m, 1H), 7.47 (m, 1H), 7.30 (t, 2H), 7.17 (m, 2H), 6.93 (m, 2H), 3.70-4.10 (m, 7H), 1.35-1.64 (brm, 14H) 137 556.5 3.7 CD3OD: 8.37 (s, 1H), 6.70-7.60 (m, 9H), 4.40 (m, 4H), 4.00 (m, 1H), 3.59 (m, 4H), 3.37 (m, 2H), 2.20 (m, 4H), 3.40 (m, 2H), 1.20-2.10 (m, 12H), 1.05 (m, 6H) 138 434 1.93 CD3OD: 8.75 (m, 2H), 8.55 (s, 1H), 8.39 (m, 1H), 8.00 (m, 1H), 7.54 (m, 1H), 7.46 (m, 1H), 7.19 (m, 1H), 7.03 (m, 1H), 4.77 (brS, 2H), 3.89 (t, 4H), 3.75 (t, 4H), 2.21 (brm, 1H), 0.68 (m, 2H), 0.59 (m, 2H) 139 453.1 3.6 140 464.5 3.7 DMSO-d6: 8.49 (s, 1H), 8.07 (d, 1H, J = 8 Hz), 7.56 (m, 1H), 7.50 (t, 1H, J = 8 Hz), 7.27 (m, 5H), 4.76 (m, 1H), 3.69 (br s, 4H), 1.59 (m, 2H), 1.45 (br s, 4H), 0.97 (d, 6H, J = 6 Hz). 141 483.5 4.4 142 463 3.2 DMSO-d6: 8.54 (s, 1H), 7.48 (t, 2H), 7.20 (brm, 2H), 7.69 (d, 2H), 4.40 (brs, 2H), 3.78 (m, 4H), 3.73 (s, 3H), 3.67 (m, 4H), 1.90 (brm, 1H), 0.47 (brm, 4H) 143 475.2 3.7 DMSO-d6: 7.60 (m, 1H), 7.27-7.40 (m, 3H), 7.08 (m, 3H), 6.43 (d, 2H), 4.74 (d, 1H), 4.10 (d, 1H), 3.94 (m, 1H), 3.72 (m, 4H), 3.66 (m, 4H), 2.32 (s, 3H), 1.00-1.60 (m, 8H) 144 479 2.94 CD3OD: 8.45 (s, 1H), 7.65& 6.90 (2 × t, 1H), 7.49 (m, 1H), 7.26 (m, 1H), 7.10 (m, 1H), 6.61 (d, 1H), 6.72&6.45 (2 × s, 1H), 4.58 (brs, 1H), 4.28 (brs, 1H), 3.90 (m, 4H), 3.74-3.78 (m, 11H), 3.449brS, 1H), 2.67 (t, 1H), 2.45 (brs, 1H) 145 447.1 3.89 CD3OD: 7.35-7.50 (m, 2H), 7.01-7.25 (m, 5H), 6.94 (d, 1H), 5.00 (d, 1H), 4.05 (d, 1H), 3.84 (m, 4H), 3.72 (m, 4H), 2.36 (s, 3H), 1.90 (m, 1H), 0.45 (m, 3H), 0.30 (m, 1H) 146 493.4 3.9 DMSO-d6: 8.47 (s, 1H), 7.34-7.55 (m, 4H), 6.62 (m, 1H), 6.46 (m, 1H), 6.29 (s, 1H), 5.95 (s, 2H), 3.77 (m, 7H), 1.63 (m, 2H), 1.53 (m, 4H), 0.83 (m, 6H) 147 488 2.5 DMSO-d6 7.53 (s, 1H), 6.45-6.60 (m, 2H), 6.16-6.30 (m, 5H), 6.03 (m, 2H), 3.75-4.10 (m, 4H), 3.14 (m, 1H), 2.10-2.65 (m, 6H), 1.95 (s, 3H), 0.35-0.70 (m, 10 H) 148 474 2.4 DMSO-d6 8.53 (s, 1H), 7.54-7.58 (m, 2H), 7.18-7.30 (m, 5H), 6.98-7.04 (m, 2H), 4.90-5.10 (m, 2H), 4.05-4.40 (m, 3H), 3.05-3.70 (m, 6H), 2.95 (s, 3H), 1.30-1.70 (m, 8H) 149 429.4 3.8 150 419.4 3.2 CD3OD: 8.65 (br s, 1H), 6.82-7.60 (br m, 8H), 4.81 (m, 1H), 3.92 (t, 4H), 3.77 (t, 4H), 2.61 (br s, 1H), 2.34 (br s, 1H), 1.17 (br s, 3H). 151 531.5 4 DMSO-d6: 8.30 (s, 1H), 7.53 (m, 1H), 7.35 (m, 1H), 7.27 (m, 2H), 6.63 (m, 1H), 6.21 (m, 1H), 6.00 (br s, 1H), 4.72 (m, 1H), 4.18 (s, 4H), 3.25 (m, 2H), 2.07 (s, 1H), 1.85 (m, 1H), 1.67 (m, 2H), 1.60 (m, 3H), 1.56 (m, 1H), 1.45 (m, 3H), 1.24 (m, 3H), 0.92 (br s, 6H). 152 462.5 3 DMSO-d6: 8.35 (s, 1H), 7.49 (m, 1H), 7.36 (s, 1H), 7.27 (m, 2H), 6.98 (m, 1H), 6.55 (d, 1H, J = 7 Hz), 6.03 (s, 2H), 4.71 (m, 1H), 3.84 (m, 2H), 3.67 (m, 2H), 2.77 (s, 6H), 1.58 (m, 2H), 1.46 (m, 2H), 0.97 (br s, 6H). 153 422.2 2.6 154 529.5 4.5 DMSO-d6: 8.31 (s, 1H), 7.55 (m, 1H), 7.34 (m, 1H), 7.28 (m, 1H), 7.10 (m, 1H), 6.78 (m, 1H), 6.22 (br d, 2H), 4.61 (br s, 1H), 4.14 (br s, 4H), 3.64 (s, 3H), 3.25 (br d, 2H), 1.69 (m, 1H), 1.4-1.8 (m, 6H), 1.3-1.35 (br m, 6H), 1.24 (br s, 8H). 155 445.4 4 156 445.1 3.9 DMSO-d6: 8.43 (s, 1H), 7.50 (m, 2H), 7.15-7.26 (m, 5H), 7.06 (m, 2H), 5.88 (m, 2H), 5.14 (m, 4H), 4.08-4.40 (m, 5H), 3.98 (m, 1H), 1.03 (m, 6H) 157 477 3.9 DMSO-d6: 8.48 (s, 1H), 7.56 (m, 2H), 7.17-7.33 (m, 5H), 6.94 (m, 2H), 4.11 (brS, 7H), 2.65 (m, 4H), 1.30-1.5 (brm, 8H) 158 447.5 3.6 159 461 3.78 DMSO-d6: 1.35 (brm, 4H), 1.51 (brm, 4H), 3.67 (brm, 4H), 3.76 (brm, 4H), 4.03 (brm, 1H), 6.91 (brm, 2H), 7.16 (brm, 3H), 7.31 (m, 2H), 7.48 (m, 1H), 7.57 (m, 1H), 8.49 (s, 1H) 160 451.4 3.2 CD3OD: 8.36 (s, 1H), 7.53 (m 1H), 7.36 (m, 1H), 7.25 (m, 1H), 7.19 (m, 1H), 7.07 (m, 1H), 6.78 (m, 1H), 6.24 (m, 1H), 6.10 (m, 1H), 4.81 (m, 1H), 3.76 (m, 4H), 3.68 (m, 7H), 1.07 (br m, 6H). 161 489 3.9 DMSO-d6: 8.56 (s, 1H), 7.45 (m, 2H), DMSO-d6: 7.27 (d, 2H), 7.10 (brm, 2H), 7.00 (d, 2H), 4.46 (brs, 2H), 3.77 (m, 4H), 3.67 (m, 4H), 1.95 (brm, 1H), 0.48 (brm, 4H) 162 516.3 4.4 DMSO-d6: 8.42 (s, 1H), 7.52 (m, 2H), 7.25 (m, 2H), 7.08 (m, 1H), 6.74 (m, 2H), 6.50 (m, 1H), 4.26-4.90 (m, 6H), 4.19 (m, 1H), 3.71 (s, 3H), 1.20-1.90 (m, 12H), 0.90 (m, 6H) 163 447.1 3.5 DMSO-d6: 8.55 (s, 1H), 7.48 (m, 2H), 7.15 (m, 3H), 7.04 (d, 1H), 6.95 (m, 1H), 6.84 (d, 1H), 4.45 (brs, 2H), 3.78 (m, 4H), 3.67 (m, 4H), 2.26 (s, 3H), 2.15 (brm, 1H), 0.48 (m, 4H) 164 479 3.6 CD3OD: 8.45 (s, 1H), 7.40 (m, 2H), 6.95-7.15 (m, 4H), 6.81 (d, 2H), 4.53 (brs, 2H), 4.21 (m, 4H), 2.65 (m, 4H), 1.85 (brm, 1H), 0.51 (brm, 4H). 165 477.5 3.8 DMSO-d6: 8.41 (s, 1H), 7.55 (m, 1H), 7.26 (m, 3H), 7.18 (m, 1H), 7.07 (m, 1H), 6.71 (s, 1H), 6.39 (br s, 1H), 4.76 (br s, 1H), 3.62 (br s, 4H), 3.58 (br s, 4H), 1.12 (s, 9H), 0.97 (d, 6H, J = 5 Hz). 166 532.2 2.5 DMSO-d6: 8.51 (s, 1H), 7.65 (m, 2H), 7.29 (m, 2H), 7.07 (m, 1H), 6.74 (m, 2H), 6.47 (m, 1H), 4.78 (m, 2H), 4.09 (m, 1H), 3.87 (s, 3H), 3.56 (brm, 5H), 3.12 (m, 2H), 2.98 (m, 2H), 1.53-2.25 (m, 8H), 0.91 (m, 6H) 167 448 2.3 DMSO-d6: 8.61 (s, 1H), 7.45-7.60 (m, 2H), 7.15-7.45 (m, 5H), 6.94 (m, 2H), 4.74-7.80 (m, 4H), 3.85 (m, 1H), 3.50 (m, 2H), 3.30 (m, 2H), 3.10 (m, 2H), 2.85 (s, 3H), 0.90 (brS, 6H) 168 474.1 2.8 169 477.5 3.5 DMSO-d6: 8.40 (s, 1H), 7.54 (m, 1H), 7.39 (m, 1H), 7.28 (m, 2H), 7.13 (t, 1H, J = 8 Hz), 6.80 (d, 1H, J = 7 Hz), 6.35 (d, 1H, J = 7 Hz), 6.25 (s, 1H), 4.61 (m, 1H), 3.73 (br s, 4H), 3.65 (s, 3H), 3.60 (d, 4H, J = 4 Hz), 1.72 (br s, 2H), 1.43 (br s, 4H), 1.29 (br s, 2H). 170 475 3.98 NMR 1H (CDCl3): “show rotameres” 8.8 (s, 1H), 8.3 (d, 2H), 7.2-7.4 (m, 5H), 6.7-7.0 (m, 2H), 4.4-4.8 (m, 2H), 3.7-4.0 (M, 8H), 3.2 (m, 2H), 1.0-1.5 (m, 12H). 171 477.5 3.5 DMSO-d6: 8.32 (s, 1H), 7.54 (m, 1H), 7.35 (m, 1H), 7.27 (m, 2H), 6.64 (d, 1H, J = 8 Hz), 6.23 (m, 1H), 6.02 (s, 1H), 4.73 (m, 1H), 4.19 (s, 4H), 3.69 (br s, 4H), 1.60 (br s, 2H), 1.47 (br s, 4H), 0.92 (d, 6H, J = 6 Hz). 172 431.4 3.3 DMSO-d6: 8.41 (s, 1H), 7.52 (m, 2H), 7.29 (m, 2H), 3.76 (m, 4H), 3.67 (m, 5H), 2.81 (br s, 1H), 2.72 (br s, 1H), 1.48 (br s, 1H), 1.24 (s, 6H), 1.13 (m, 2H), 0.86 (m, 1H). 173 536.2 3.7 CD3OD: 8.38 (s, 1H), 7.75 (m, 1H), 7.10-7.65 (10H), 7.15 (m, 1H), 3.85 (brs, 2H), 3.55 (m, 3H), 2.98 (m, 2H), 0.89 (brm, 6H) 174 357 2.77 DMSO-d6: 1.60 (m, 2H), 1.83 (m, 2H), 2.10 (m, 2H), 3.66 (m, 4H), 3.78 (m, 4H), 7.17 (m, 1H), 7.27 (t, 1H), 7.46 (m, 1H), 7.53 (m, 1H), 8.23 (d, 1H), 8.53 (s, 1H) 175 465.4 3.8 DMSO-d6: 8.42 (s, 1H), 7.50 (m, 2H), 7.42 (t, 1H, J = 7 Hz), 7.34 (d, 1H, J = 7 Hz), 7.13 (t, 1H, J = 8 Hz), 6.80 (d, 1H, J = 7 Hz), 6.30 (d, 1H, J = 7 Hz), 6.14 (s, 1H), 4.66 (br s, 1H), 3.68 (br s, 4H), 3.66 (s, 3H), 1.59 (m, 2H), 1.46 (br s, 4H), 0.88 (d, 6H, J = 6 Hz). 176 501 2.6 DMSO-d6: 8.63 (s, 1H), 7.45 (m, 2H), 7.26 (d, 2H), 7.17 (m, 2H), 6.99 (d, 2H), 4.77 (d, 2H), 4.48 (brs, 2H), 3.51 (m, 2H), 4.48 (m, 2H), 3.51 (m, 2H), 3.31 (m, 2H), 3.15 (m, 2H), 2.84 (s, 3H), 2.00 (m, 1H), 1.28 (s, 9H), 0.48 (m, 4H). 177 475.5 3.72 178 466.4 3.2 DMSO-d6: 8.55 (s, 1H), 8.08 (d, 1H, J = 8 Hz) 7.58 (m, 1H), 7.51 (m, 1H), 7.28 (m, 5H), 4.76 (br s, 1H), 3.67 (br s, 4H), 3.59 (d, 4H, J = 4 Hz), 0.98 (d, 6H, J = 4 Hz). 179 433.4 3.7 DMSO-d6: 7.57 (m, 1H), 7.37 (m, 2H), 7.29 (m, 2H), 7.19 (m, 1H), 7.14 (t, 2H, J = 8 Hz), 6.35 (br s, 1H), 4.78 (m, 1H), 3.79 (br s, 2H), 3.62 (br s, 2H), 2.41 (s, 3H), 1.56 (m, 2H), 1.42 (m, 4H), 0.85 (dd, 6H, J = 7 Hz, 16 Hz). 180 459 2.4 DMSO-d6 8.49 (s, 1H), 7.57 (m, 2H), 7.32 (t, 2H), 7.21 (m, 3H), 6.98 (m, 2H), 4.77 (m, 2H), 4.65 (m, 1H), 4.20 (m, 2H), 3.51 (m, 2H), 3.33 (m, 2H), 3.11 (m, 2H), 2.85 (s, 3H), 2.05 (m, 2H), 1.25-1.50 (4H) 181 459.4 3.5 182 465.4 3.1 DMSO-d6: 8.40 (s, 1H), 7.54 (m, 1H), 7.39 (m, 1H), 7.29 (m, 2H), 6.71 (d, 1H, J = 7 Hz), 6.18 (m, 2H), 6.01 (s, 2H), 4.73 (m, 1H), 3.66 (br s, 4H), 3.61 (br s, 4H), 0.93 (d, 6H, J = 6 Hz). 183 449.4 3.1 DMSO-d6: 8.48 (s, 1H), 7.55 (m, 1H), 7.42 (t, 1H, J = 7 Hz), 7.29 (m, 2H), 7.13 (t, 1H, J = 8 Hz), 6.76 (dd, 1H, J = 2 Hz, 8 Hz), 6.40 (d, 1H, J = 8 Hz), 6.37 (s, 1H), 3.72 (t, 4H, J = 5 Hz), 3.67 (s, 3H), 3.64 (t, 4H, J = 5 Hz), 2.85 (m, 1H), 0.67 (m, 2H), 0.39 (m, 2H). 184 515.5 4.2 DMSO-d6: 8.45 (s, 1H), 7.60 (m, 2H), 7.20 (m, 2H), 6.99 (d, 2H), 6.81 (d, 2H), 4.30 (m, 4H), 3.73 (s, 3H), 3.40 (m, 2H), 2.06 (m, 1H), 1.25-1.90 (m, 12H), 0.46 (brm, 4H) 185 451.5 3.2 DMSO-d6: 8.35 (s, 1H), 7.55 (m, 1H), 7.39 (m, 1H), 7.29 (m, 2H), 6.75 (d, 2H, J = 8 Hz), 6.63 (d, 2H, J = 8 Hz), 4.76 (m, 1H), 3.70 (s, 3H), 3.64 (br s, 4H), 3.60 (br s, 4H), 0.92 (d, 6H, J = 6 Hz). 186 479.2 3.4 DMSO-d6: 7.04-7.60 (m, 6H), 6.72 (m, 2H), 6.31 (d, 2H), 4.52 (d, 1H), 4.22 (d, 1H), 3.62-3.82 (m, 11H), 2.34 (s, 3H), 0.95 (d, 3H), 0.51 (d, 3H) 187 405 3.21 CDCl3: 8.43 (s, 1H), 7.61 (t, 1H), 7.28 (m, 1H), 7.12-7.21 (m, 4H), 7.05 (d, 1H), 6.96 (m, 1H), 4.79 (s, 2H), 4.55 (s, 2H), 3.85 (t, 4H), 3.72 (t, 4H), 188 499.1 3.6 DMSO-d6: 8.36 (s, 1H), 7.05-7.60 (m, 10H), 6.72 (2H), 5.17 (m, 1H), 4.36 (m, 2H), 3.89 (m, 1H), 3.69 (s, 3H), 1.45 (m, 3H), 0.79 (m, 6H) 189 501.5 4.2 190 463.4 3.4 DMSO-d6: 8.37 (s, 1H), 7.54 (m, 1H), 7.41 (t, 1H, J = 7 Hz), 7.29 (m, 2H), 7.18, (t, 1H, J = 6 Hz), 6.82 (d, 1H, J = 8 Hz), 6.36 (d, 1H, J = 8 Hz), 6.28 (s, 1H), 4.66 (m, 1H), 3.67 (m, 7H), 3.61 (m, 4H), 1.98 (m, 2H), 1.69 (m, 2H), 1.52 (m, 1H), 1.42 (m, 1H). 191 465.1 3.4 DMSO-d6: 8.46 (brs, 1H), 7.55 (brm, 2H), 7.30 (brm, 3H), 7.12 (brm, 3H), 4.35 (m, 1H), 3.65-3.80 (m, 12H), 1.50-1.80 (brm, 4H) 192 487.5 3.6 CD3OD: 7.36 (m, 2H), 7.06 (m, 2H), 6.82 (s, 1H), 6.73 (d, 1H), 6.53 (d, 1H), 4.95 (d, 1H), 4.52 (t, 2H), 3.94 (d, 1H), 3.84 (m, 4H), 3.12 (m, 2H), 2.35 (s, 3H), 1.87 (m, 1H), 1.70 (m, 2H), 1.61 (m, 4H), 0.51 (3H), 0.20 (m, 1H) 193 476 2.2 DMSO-d6 8.62 (s, 1H), 7.47 (m, 2H), 7.22 (m, 2H), 6.98 (d, 2H), 6.80 (d, 2H), 4.76 (d, 2H), 4.45 (brm, 2H), 3.74 (d, 3H), 3.51 (m, 2H), 3.30 (m, 2H), 2.84 (s, 3H), 1.95 (m, 1H), 0.47 (brm, 4H). 194 451.1 3.5 195 501 3.6 DMSO-d6: 8.65 (brs, 1H), 7.61 (d, 1H), 7.50 (m, 4H), 7.38 (d, 1H), 7.05-7.15 (m, 2H), 4.60 (brs, 2H), 3.78 (m, 4H), 3.67 (m, 4H), 2.20 (brm, 1H), 0.53 (m, 4H) 196 385 3.11 DMSO-d6: 1.06-1.23 (m, 5H), 1.51 (m, 1H), 1.61-1.69 (m, 4H), 1.70 (m, 2H), 3.54 (m, 1H), 3.66 (m, 4H), 3.77 (m, 4H), 7.17 (m, 1H), 7.25 (t, 1H), 7.46 (m, 1H), 7.53 (m, 1H), 7.85 (d, 1H), 8.50 (s, 1H) 197 493.5 2.9 DMSO-d6: 8.69 (s, 1H), 7.56 (m, 1H), 7.39 (m, 1H), 7.29 (m, 2H), 7.16 (m, 1H), 6.83 (d, 1H, J = 7 Hz), 6.35 (d, 1H, J = 7 Hz), 6.27 (s, 1H), 4.55 (br s, 1H), 3.82 (m, 2H), 3.66 (s, 3H), 3.45 (br s, 8H), 3.33 (m, 2H), 1.59 (m, 2H), 1.28 (m, 2H). 198 518.5 3.2 DMSO-d6: 8.45 (d, 2H), 7.34-7.55 (m, 4H), 6.67 (m, 2H), 6.63 (m, 2H), 3.77-3.98 (m, 11H), 3.17 (t, 4H), 1.93 (t, 4H), 2.20 (brm, 1H), 1.63 (brm, 2H), 1.53 (brm, 4H), 0.82 (brm, 6H) 199 421.2 3.2 DMSO-d6: 8.33 (s, 1H), 7.03-7.53 (m, 9H), 3.77 (m, 4H), 3.67 (m, 4H), 3.49 (m, 1H), 2.73 (s, 3H), 2.66 (m, 2H) 200 489.2 3.3 DMSO-d6: 7.10-7.60 (m, 3H), 6.51-6.66 (m, 3H), 4.83 (d, 1H), 4.48 (t, 2H), 3.89 (d, 1H), 3.64-3.73 (m, 8H), 2.29 (s, 3H), 1.84 (m, 1H), 0.20-0.50 (m, 4H) 201 437.4 3.6 CD3OD: 8.33 (s, 1H), 7.54 (q, 1H, J = 6 Hz, 13 Hz), 7.35 (br s, 1H), 7.09-7.30 (m, 5H), 6.60 (br s, 2H), 4.86 (m, 1H), 4.09 (br s, 4H), 2.56 (br s, 4H), 1.06 (d, 6H, J = 6 Hz). 202 446.4 3.1 DMSO-d6: 8.51 (s, 1H), 7.69 (d, 1H, J = 7 Hz), 7.63 (m, 1H), 7.40 (m, 1H), 7.32 (t, 3H, J = 9 Hz), 7.05 (m, 1H), 6.8 (br s, 1H), 4.75 (br s, 1H), 3.67 (d, 4H, J = 5 Hz), 3.61 (d, 4H, J = 5 Hz), 0.96 (d, 6H, J = 6 Hz). 203 507.5 3.6 DMSO-d6: 8.41 (s, 1H), 7.51 (m, 1H), 7.43 (m, 2H), 7.17 (m, 1H), 6.83 (d, 1H, J = 7 Hz), 6.62 (d, 1H, J = 2 Hz), 6.33 (d, 1H, J = 7 Hz), 6.19 (s, 1H), 4.54 (br s, 1H), 3.82 (m, 2H), 3.75 (m, 4H), 3.68 (s, 3H), 3.26 (m, 2H), 1.65 (m, 1H), 1.54-1.59 (m, 4H), 1.45 (m, 4H), 1.22 (m, 3H). 204 526.1 2.37 DMSO-d6: 8.87 (d, 2H), 8.51 (s, 1H), 8.34 (m, 2H), 7.89 (m, 2H), 7.58 (t, 1H), 7.56 (m, 2H), 7.48 (m, 1H), 7.05 (m, 1H), 7.85 (m, 1H), 4.73 (brs, 2H), 4.22 (m, 4H), 2.65 (brm, 4H), 2.05 (m, 1H), 0.63 (m, 2H), 0.56 (m, 2H) 205 434 2 DMSO-d6: 8.75 (brs, 1H), 8.62 (d, 2H), 7.52 (m, 2H), 7.41 (m, 2H), 7.26 (m, 2H), 4.64 (brs, 2H), 3.78 (m, 4H), 3.67 (m, 4H), 2.45 (brm, 1H), 0.57 (m, 4H) 206 421 3.65 CDCl3: 8.41 (s, 1H), 7.59 (t, 1H), 7.29 (m, 1H), 7.12-7.21 (m, 4H), 7.05 (d, 1H), 6.96 (m, 1H), 4.79 (s, 2H), 4.55 (s, 2H), 4.17 (t, 4H), 2.63 (t, 4H), 207 475.4 3.72

VI. Assays for Detecting and Measuring Inhibition Properties of Compounds

A. Optical Methods for Assaying CaV Inhibition Properties of Compounds:

Compounds of the embodiments are useful as antagonists of voltage-gated calcium ion channels. Antagonist properties of test compounds were assessed as follows. Cells expressing the CaV of interest were placed into microtiter plates. After an incubation period, the cells were stained with fluorescent dyes sensitive to the transmembrane potential. The test compounds were added to the microtiter plate. The cells were stimulated with electrical means to evoke a CaV dependent membrane potential change from unblocked channels, which was detected and measured with trans-membrane potential-sensitive dyes. Antagonists were detected as a decreased membrane potential response to the stimulus. The optical membrane potential assay utilized voltage-sensitive FRET sensors described by Gonzalez and Tsien (See, Gonzalez, J. E. and R. Y. Tsien (1995) “Voltage sensing by fluorescence resonance energy transfer in single cells” Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y. Tsien (1997) “Improved indicators of cell membrane potential that use fluorescence resonance energy transfer” Chem Biol 4(4): 269-77) in combination with instrumentation for measuring fluorescence changes such as the Voltage/Ion Probe Reader (VIPR®) (See, Gonzalez, J. E., K. Oades, et al. (1999) “Cell-based assays and instrumentation for screening ion-channel targets” Drug Discov Today 4(9): 431-439).

VIPR® Optical Membrane Potential Assay Method with Electrical Stimulation

The following is an example of how CaV2.2 inhibition activity is measured using the optical membrane potential method. Other subtypes are performed in an analogous mode in a cell line expressing the CaV of interest.

HEK293 cells stably expressing CaV2.2 are plated into 96-well microtiter plates. After an appropriate incubation period, the cells are stained with the voltage sensitive dyes CC2-DMPE/DiSBAC2(3) as follows.

Reagents:

100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO

10 mM DiSBAC₆(3) (Aurora #00-100-010) in dry DMSO 10 mM CC2-DMPE (Aurora #00-100-008) in dry DMSO 200 mM Acid Yellow 17 (Aurora #VABSC) in H₂0 370 mM Barium Chloride (Sigma Cat# B6394) in H₂0 Bath X 160 mM NaCl (Sigma Cat# S-9888) 4.5 mM KCl (Sigma Cat# P-5405) 1 mM MgCl2 (Fluke Cat#63064) 10 mM HEPES (Sigma Cat# H-4034)

pH 7.4 using NaOH

Loading Protocol:

2×CC2-DMPE=20 μM CC2-DMPE:

10 mM CC2-DMPE is vortexed with an equivalent volume of 10% Pluronic, followed by vortexing in required amount of HBSS containing 10 mM HEPES. Each cell plate will require 5 mL of 2×CC2-DMPE. 50 μL of 2×CC2-DMPE is added to wells containing washed cells, resulting in a 10 μM final staining concentration. The cells are stained for 30 minutes in the dark at RT.

2×CC2DMPE & DISBAC₆(3)=8 μM CC2DMPE & 2.5 μM DISBAC₆(3):

Vortex together both dyes with an equivalent volume of 10% Pluronic (in DMSO). Vortex in required amount of Bath X with beta-cyclodextrin. Each 96 well cell plate will require 5 ml of 2×CC2DMPE. Wash plate with ELx405 with Bath X, leaving a residual volume of 50 μL/well. Add 50 AL of 2XCC2DMPE & DISBAC₆(3) to each well. Stain for 30 minutes in the dark at RT.

1.5×AY17=750 μM AY17 with 15 mM BaCl₂:

Add Acid Yellow 17 to vessel containing Bath X. Mix well. Allow solution to sit for 10 minutes. Slowly mix in 370 mM BaCl₂. This solution can be used to solvate compound plates. Note that compound plates are made at 1.5× drug concentration and not the usual 2×. Wash CC2 stained plate, again, leaving residual volume of 50 μL. Add 100 uL/well of the AY17 solution. Stain for 15 minutes in the dark at RT. Run plate on the optical reader.

The electrical stimulation instrument and methods of use are described in ION Channel Assay Methods PCT/US01/21652, herein incorporated by reference. The instrument comprises a microtiter plate handler, an optical system for exciting the coumarin dye while simultaneously recording the coumarin and oxonol emissions, a waveform generator, a current- or voltage-controlled amplifier, and a device for inserting electrodes in well. Under integrated computer control, this instrument passes user-programmed electrical stimulus protocols to cells within the wells of the microtiter plate.

Assay Protocol

Insert or use electrodes into each well to be assayed.

Use the current-controlled amplifier to deliver stimulation wave pulses for 3-5 s. Two seconds of pre-stimulus recording are performed to obtain the un-stimulated intensities. Five seconds of post-stimulation recording are performed to examine the relaxation to the resting state.

Data Analysis

Data are analyzed and reported as normalized ratios of background-subtracted emission intensities measured in the 460 nm and 580 nm channels. Background intensities are then subtracted from each assay channel. Background intensities are obtained by measuring the emission intensities during the same time periods from identically treated assay wells in which there are no cells. The response as a function of time is then reported as the ratios obtained using the following formula:

${R(t)} = \frac{\left( {{intensity}_{460\mspace{14mu} {nm}} - {background}_{\; {460\mspace{14mu} {nm}}}} \right)}{\left( {{intensity}_{580\mspace{14mu} {nm}} - {background}_{\; {580\mspace{14mu} {nm}}}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final (R_(f)) ratios. These are the average ratio values during part or all of the pre-stimulation period, and during sample points during the stimulation period. The response to the stimulus R=R_(f)/R_(i) is then calculated.

Control responses are obtained by performing assays in the presence of a compound with the desired properties (positive control), such as mibefradil, and in the absence of pharmacological agents (negative control). Responses to the negative (N) and positive (P) controls are calculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$

where R is the ratio response of the test compound.

Electrophoresiology Assays for CaV Activity and Inhibition of Test Compounds

Patch clamp electrophysiology was used to assess the efficacy of calcium channel blockers expressed in HEK293 cells. HEK293 cells expressing CaV2.2 have been visually identified and probed with fine tip glass electrodes connected to an amplifier (Axon Instruments). The “voltage clamp” mode has been used to assess the compound's IC50 holding the cells at −100 mV. The results of these experiments have contributed to the definition of the efficacy profile of the compounds.

Voltage-Clamp Assay in HEK293 Cells Expressing CaV2.2

CaV2.2 calcium currents were recorded from HEK293 cells using the whole-cell variation of the patch clamp technique. Recordings were made at room temperature (˜22° C.) with thick walled borosilicate glass electrodes (WPI; resistance 3-4 MΩ using an Axopatch 200B amplifier (Axon Instruments). After establishing the whole-cell configuration, approximately 15 minutes were allowed for the pipette solution to equilibrate within the cell before beginning recording. Currents were lowpass filtered between 2-5 kHz and digitally sampled at 10 kHz. Series resistance was compensated 60-70% and was monitored continuously throughout the experiment. The liquid junction potential (−7 mV) between the intracellular pipette solution and the external recording solution was not accounted for in the data analysis. Test solutions were applied to the cells with a gravity driven fast perfusion system (SF-77; Warner Instruments).

Dose-response relationships were determined in voltage clamp mode by repeatedly depolarizing the cell from the experiment specific holding potential to a test potential of +20 mV for 50 ms at frequencies of 0.1, 1, 5, 10, 15, and 20 Hz. Blocking effects were allowed to plateau before proceeding to the next test concentration.

Solutions

Intracellular solution (in mM): Cs—F (130), NaCl (10), MgCl₂ (1), EGTA (1.5), CaCl₂ (0.1), HEPES (10), glucose (2), pH=7.42, 290 mOsm.

Extracellular solution (in mM): NaCl (138), BaCl₂ (10), KCl (5.33), KH₂PO₄ (0.44), MgCl₂ (0.5), MgSO₄ (0.41), NaHCO₃ (4), Na₂HPO₄ (0.3), glucose (5.6), HEPES (10).

(A) Following these procedures, representative compounds of the embodiments were found to possess desired N-type calcium channel modulation activity and selectivity.

B. Assays for Detecting and Measuring NaV Inhibition Properties of Compounds

Optical Methods for Assaying NaV Inhibition Properties of Compounds:

Compounds of the invention are useful as antagonists of voltage-gated sodium ion channels. Antagonist properties of test compounds were assessed as follows. Cells expressing the NaV of interest were placed into microtiter plates. After an incubation period, the cells were stained with fluorescent dyes sensitive to the transmembrane potential. The test compounds were added to the microtiter plate. The cells were stimulated with either chemical or electrical means to evoke a NaV dependent membrane potential change from unblocked channels, which was detected and measured with trans-membrane potential-sensitive dyes. Antagonists were detected as a decreased membrane potential response to the stimulus. The optical membrane potential assay utilized voltage-sensitive FRET sensors described by Gonzalez and Tsien (See, Gonzalez, J. E. and R. Y. Tsien (1995) “Voltage sensing by fluorescence resonance energy transfer in single cells” Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y. Tsien (1997) “Improved indicators of cell membrane potential that use fluorescence resonance energy transfer” Chem Biol 4(4): 269-77) in combination with instrumentation for measuring fluorescence changes such as the Voltage/Ion Probe Reader (VIPR®) (See, Gonzalez, J. E., K. Oades, et al. (1999) “Cell-based assays and instrumentation for screening ion-channel targets” Drug Discov Today 4(9): 431-439).

VIPR® Optical Membrane Potential Assay Method with Chemical Stimulation

Cell Handling and Dye Loading

24 hours before the assay on VIPR, CHO cells endogenously expressing a NaV 1.2 type voltage-gated NaV are seeded in 96-well poly-lysine coated plates at 60,000 cells per well. Other subtypes are performed in an analogous mode in a cell line expressing the NaV of interest.

-   1) On the day of the assay, medium is aspirated and cells are washed     twice with 225 μL of Bath Solution #2 (BS#2). -   2) A 15 μM CC2-DMPE solution is prepared by mixing 5 mM coumarin     stock solution with 10% Pluronic 127 1:1 and then dissolving the mix     in the appropriate volume of BS#2. -   3) After bath solution is removed from the 96-well plates, the cells     are loaded with 80 μL of the CC2-DMPE solution. Plates are incubated     in the dark for 30 minutes at room temperature. -   4) While the cells are being stained with coumarin, a 15 μL oxonol     solution in BS#2 is prepared. In addition to DiSBAC₂(3), this     solution should contain 0.75 mM ABSC1 and 30 μL veratridine     (prepared from 10 mM EtOH stock, Sigma #V-5754). -   5) After 30 minutes, CC2-DMPE is removed and the cells are washed     twice with 225 μL of BS#2. As before, the residual volume should be     40 μL. -   6) Upon removing the bath, the cells are loaded with 80 μL of the     DiSBAC₂(3) solution, after which test compound, dissolved in DMSO,     is added to achieve the desired test concentration to each well from     the drug addition plate and mixed thoroughly. The volume in the well     should be roughly 121 μL. The cells are then incubated for 20-30     minutes. -   7) Once the incubation is complete, the cells are ready to be     assayed on VIPR® with a sodium addback protocol. 120 μL of Bath     solution #1 is added to stimulate the NaV dependent depolarization.     200 μL tetracaine was used as an antagonist positive control for     block of the NaV channel.

Analysis of VIPR Data:

Data are analyzed and reported as normalized ratios of background-subtracted emission intensities measured in the 460 nm and 580 nm channels. Background intensities are then subtracted from each assay channel. Background intensities are obtained by measuring the emission intensities during the same time periods from identically treated assay wells in which there are no cells. The response as a function of time is then reported as the ratios obtained using the following formula:

${R(t)} = \frac{\left( {{intensity}_{460\mspace{14mu} {nm}} - {background}_{\; {460\mspace{14mu} {nm}}}} \right)}{\left( {{intensity}_{580\mspace{14mu} {nm}} - {background}_{\; {580\mspace{14mu} {nm}}}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final (R_(f)) ratios. These are the average ratio values during part or all of the pre-stimulation period, and during sample points during the stimulation period. The response to the stimulus R_(r)=R_(f)/R_(i) is then calculated. For the Na⁺ addback analysis time windows, baseline is 2-7 sec and final response is sampled at 15-24 sec.

Control responses are obtained by performing assays in the presence of a compound with the desired properties (positive control), such as tetracaine, and in the absence of pharmacological agents (negative control). Responses to the negative (N) and positive (P) controls are calculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$

where R is the ratio response of the test compound

Solutions [mM]:

-   Bath Solution #1: NaCl 160, KCl 4.5, CaCl₂ 2, MgCl₂ 1, HEPES 10, pH     7.4 with NaOH -   Bath Solution #2 TMA-Cl 160, CaCl₂ 0.1, MgCl₂ 1, HEPES 10, pH 7.4     with KOH (final K concentration ˜5 mM) -   CC2-DMPE: prepared as a 5 mM stock solution in DMSO and stored at     −20° C. -   DiSBAC₂(3): prepared as a 12 mM stock in DMSO and stored at −20° C. -   ABSC1: prepared as a 200 mM stock in distilled H₂O and stored at     room temperature

Cell Culture

CHO cells are grown in DMEM (Dulbecco's Modified Eagle Medium; GibcoBRL #10569-010) supplemented with 10% FBS (Fetal Bovine Serum, qualified; GibcoBRL #16140-071) and 1% Pen-Strep (Penicillin-Streptomycin; GibcoBRL #15140-122). Cells are grown in vented cap flasks, in 90% humidity and 10% CO₂, to 100% confluence. They are usually split by trypsinization 1:10 or 1:20, depending on scheduling needs, and grown for 2-3 days before the next split.

VIPR® Optical Membrane Potential Assay Method with Electrical Stimulation

The following is an example of how NaV1.3 inhibition activity is measured using the optical membrane potential method#2. Other subtypes are performed in an analogous mode in a cell line expressing the NaV of interest.

HEK293 cells stably expressing NaV 1.3 are plated into 96-well microtiter plates. After an appropriate incubation period, the cells are stained with the voltage sensitive dyes CC2-DMPE/DiSBAC2(3) as follows.

Reagents:

-   -   100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO     -   10 mM DiSBAC₂(3) (Aurora #00-100-010) in dry DMSO     -   10 mM CC2-DMPE (Aurora #00-100-008) in dry DMSO     -   200 mM ABSC1 in H₂0     -   Hank's Balanced Salt Solution (Hyclone #SH30268.02) supplemented         with 10 mM HEPES (Gibco #15630-080)

Loading Protocol:

2×CC2-DMPE=20 μM CC2-DMPE:

10 mM CC2-DMPE is vortexed with an equivalent volume of 10% pluronic, followed by vortexing in required amount of HBSS containing 10 mM HEPES. Each cell plate will require 5 mL of 2×CC2-DMPE. 50 μL of 2×CC2-DMPE is added to wells containing washed cells, resulting in a 10 μM final staining concentration. The cells are stained for 30 minutes in the dark at RT.

2×DISBAC₂(3) with ABSC1=6 μM DISBAC₂(3) and 1 mM ABSC1:

The required amount of 10 mM DISBAC₂(3) is added to a 50 ml conical tube and mixed with 1 μL 10% pluronic for each mL of solution to be made and vortexed together. Then HBSS/HEPES is added to make up 2× solution. Finally, the ABSC1 is added.

The 2×DiSBAC₂(3) solution can be used to solvate compound plates. Note that compound plates are made at 2× drug concentration. Wash stained plate again, leaving residual volume of 50 μL. Add 50 μL/well of the 2×DiSBAC₂(3) w/ABSC1. Stain for 30 minutes in the dark at RT.

The electrical stimulation instrument and methods of use are described in ION Channel Assay Methods PCT/US01/21652, herein incorporated by reference. The instrument comprises a microtiter plate handler, an optical system for exciting the coumarin dye while simultaneously recording the coumarin and oxonol emissions, a waveform generator, a current- or voltage-controlled amplifier, and a device for inserting electrodes in well. Under integrated computer control, this instrument passes user-programmed electrical stimulus protocols to cells within the wells of the microtiter plate.

Reagents

Assay buffer #1 140 mM NaCl, 4.5 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂, 10 mM HEPES, 10 mM glucose, pH 7.40, 330 mOsm Pluronic stock (1000×): 100 mg/mL pluronic 127 in dry DMSO Oxonol stock (3333×): 10 mM DiSBAC₂(3) in dry DMSO Coumarin stock (1000×): 10 mM CC2-DMPE in dry DMSO ABSC1 stock (400×): 200 mM ABSC1 in water

Assay Protocol

-   -   1. Insert or use electrodes into each well to be assayed.     -   2. Use the current-controlled amplifier to deliver stimulation         wave pulses for 3 s. Two seconds of pre-stimulus recording are         performed to obtain the un-stimulated intensities. Five seconds         of post-stimulation recording are performed to examine the         relaxation to the resting state.

Data Analysis

Data are analyzed and reported as normalized ratios of background-subtracted emission intensities measured in the 460 nm and 580 nm channels. Background intensities are then subtracted from each assay channel. Background intensities are obtained by measuring the emission intensities during the same time periods from identically treated assay wells in which there are no cells. The response as a function of time is then reported as the ratios obtained using the following formula:

${R(t)} = \frac{\left( {{intensity}_{460\mspace{14mu} {nm}} - {background}_{\; {460\mspace{14mu} {nm}}}} \right)}{\left( {{intensity}_{580\mspace{14mu} {nm}} - {background}_{\; {580\mspace{14mu} {nm}}}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final (R_(f)) ratios. These are the average ratio values during part or all of the pre-stimulation period, and during sample points during the stimulation period. The response to the stimulus R_(r)=R_(f)/R_(i) is then calculated.

Control responses are obtained by performing assays in the presence of a compound with the desired properties (positive control), such as tetracaine, and in the absence of pharmacological agents (negative control). Responses to the negative (N) and positive (P) controls are calculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$

where R is the ratio response of the test compound.

Electrophysiology Assays for NaV Activity and Inhibition of Test Compounds

Patch clamp electrophysiology was used to assess the efficacy and selectivity of sodium channel blockers in dorsal root ganglion neurons. Rat neurons were isolated from the dorsal root ganglions and maintained in culture for 2 to 10 days in the presence of NGF (50 ng/ml) (culture media consisted of NeurobasalA supplemented with B27, glutamine and antibiotics). Small diameter neurons (nociceptors, 8-12 μm in diameter) have been visually identified and probed with fine tip glass electrodes connected to an amplifier (Axon Instruments). The “voltage clamp” mode has been used to assess the compound's IC50 holding the cells at −60 mV. In addition, the “current clamp” mode has been employed to test the efficacy of the compounds in blocking action potential generation in response to current injections. The results of these experiments have contributed to the definition of the efficacy profile of the compounds.

Voltage-Clamp Assay in DRG Neurons

TTX-resistant sodium currents were recorded from DRG somata using the whole-cell variation of the patch clamp technique. Recordings were made at room temperature (˜22° C.) with thick walled borosilicate glass electrodes (WPI; resistance 3-4 MΩ) using an Axopatch 200B amplifier (Axon Instruments). After establishing the whole-cell configuration, approximately 15 minutes were allowed for the pipette solution to equilibrate within the cell before beginning recording. Currents were lowpass filtered between 2-5 kHz and digitally sampled at 10 kHz. Series resistance was compensated 60-70% and was monitored continuously throughout the experiment. The liquid junction potential (−7 mV) between the intracellular pipette solution and the external recording solution was not accounted for in the data analysis. Test solutions were applied to the cells with a gravity driven fast perfusion system (SF-77; Warner Instruments).

Dose-response relationships were determined in voltage clamp mode by repeatedly depolarizing the cell from the experiment specific holding potential to a test potential of +10 mV once every 60 seconds. Blocking effects were allowed to plateau before proceeding to the next test concentration.

Solutions

Intracellular solution (in mM): Cs—F (130), NaCl (10), MgCl₂ (1), EGTA (1.5), CaCl₂ (0.1), HEPES (10), glucose (2), pH=7.42, 290 mOsm.

Extracellular solution (in mM): NaCl (138), CaCl₂ (1.26), KCl (5.33), KH₂PO₄ (0.44), MgCl₂ (0.5), MgSO₄ (0.41), NaHCO₃(4), Na₂HPO₄ (0.3), glucose (5.6), HEPES (10), CdCl₂ (0.4 NiCl₂ (0.1), TTX (0.25×10⁻³).

Current-Clamp Assay for NaV Channel Inhibition Activity of Compounds

Cells were current-clamped in whole-cell configuration with a Multiclamp 700A amplifier (Axon Inst). Borosilicate pipettes (4-5 MOhm) were filled with (in mM):150 K-gluconate, 10 NaCl, 0.1 EGTA, 10 HEPES, 2 MgCl₂, (buffered to pH 7.34 with KOH). Cells were bathed in (in mM): 140 NaCl, 3 KCl, 1 MgCl, 1 CaCl, and 10 HEPES). Pipette potential was zeroed before seal formation; liquid junction potentials were not corrected during acquisition. Recordings were made at room temperature.

Examples of activities of the ion channel modulators of formulae (I and Ia) on modulating CaV 2.2, NaV 1.3, and NaV 1.8 receptors are shown below in Table 9. The compound activity for the CaV 2.2, NaV 1.3, and NaV 1.8 receptors is illustrated with “+++” if activity was measured to be less than 2.0 μM, “++” if activity was measured to be 2.0 μM to 10.0 μM, “+” if activity was measured to be greater than 10.0 μM, and “−” if no data was available.

TABLE 9 Activities of the ion channel modulators of formulae (I, Ia) Compound No. CaV 2.2 NaV 1.3 NaV 1.8 1 +++ ++ ++ 2 ++ + + 3 + ++ + 4 +++ ++ ++ 5 ++ + + 6 − − − 7 ++ ++ + 8 ++ ++ + 9 ++ ++ + 10 ++ ++ + 11 + + + 12 +++ + + 13 ++ + + 14 ++ + + 15 + + + 16 + + + 17 + + + 18 + + + 19 + + + 20 +++ ++ ++ 21 + + + 22 +++ ++ + 23 + + + 24 +++ ++ ++ 25 + + + 26 ++ ++ + 27 ++ ++ + 28 + + + 29 +++ ++ ++ 30 ++ ++ + 31 ++ ++ + 32 ++ ++ + 33 + + + 34 ++ ++ + 35 + + + 36 ++ ++ + 37 + + + 38 − − − 39 + + + 40 + ++ + 41 + ++ + 42 ++ ++ + 43 ++ ++ + 44 + ++ ++ 45 + + + 46 + + + 47 ++ ++ + 48 ++ ++ + 49 + ++ + 50 ++ + + 51 ++ ++ + 52 ++ ++ + 53 ++ ++ + 54 ++ ++ + 55 ++ ++ ++ 56 ++ + + 57 + + + 58 + + + 59 +++ ++ ++ 60 ++ + + 61 − − − 62 ++ ++ + 63 + + + 64 ++ ++ + 65 ++ + + 66 ++ + + 67 + + + 68 ++ + + 69 ++ + + 70 +++ ++ + 71 + + + 72 + + + 73 + + + 74 ++ ++ + 75 + + + 76 + + + 77 ++ ++ + 78 +++ ++ ++ 79 + + + 80 ++ ++ + 81 ++ ++ + 82 ++ + + 83 +++ ++ ++ 84 + + + 85 + ++ ++ 86 ++ + + 87 + + + 88 ++ + + 89 + + + 90 ++ ++ ++ 91 + + + 92 +++ + + 93 ++ ++ + 94 +++ +++ ++ 95 ++ + + 96 +++ ++ + 97 + + + 98 +++ ++ ++ 99 + + + 100 ++ ++ + 101 ++ ++ + 102 + + + 103 +++ +++ + 104 + ++ + 105 ++ ++ + 106 + + + 107 + + + 108 +++ ++ + 109 ++ ++ + 110 ++ + + 111 + + + 112 + ++ + 113 + ++ + 114 +++ + + 115 ++ + + 116 ++ ++ + 117 +++ ++ ++ 118 +++ ++ + 119 ++ + + 120 +++ ++ + 121 ++ ++ + 122 ++ + + 123 ++ + + 124 ++ ++ + 125 ++ + + 126 ++ + + 127 ++ ++ + 128 ++ ++ + 129 + + + 130 ++ ++ + 131 +++ ++ ++ 132 + + + 133 ++ ++ + 134 +++ ++ + 135 ++ + + 136 ++ ++ + 137 +++ + + 138 + + + 139 ++ ++ ++ 140 ++ ++ + 141 ++ + + 142 +++ +++ +++ 143 ++ ++ ++ 144 + + + 145 ++ ++ + 146 ++ ++ ++ 147 ++ + + 148 ++ + + 149 + + + 150 + + + 151 ++ ++ + 152 ++ ++ + 153 + + + 154 ++ + + 155 ++ + + 156 +++ ++ ++ 157 ++ ++ + 158 + + + 159 ++ ++ ++ 160 + + + 161 ++ ++ ++ 162 +++ +++ + 163 ++ + + 164 ++ ++ ++ 165 + ++ + 166 − − − 167 + + + 168 + + + 169 + ++ + 170 + + + 171 ++ ++ + 172 + + + 173 +++ ++ + 174 + + + 175 ++ ++ + 176 ++ + + 177 + + + 178 + + + 179 + + + 180 ++ ++ + 181 + + + 182 ++ + + 183 + + + 184 ++ + + 185 ++ + + 186 ++ ++ + 187 + + + 188 +++ +++ ++ 189 ++ + + 190 + ++ + 191 + + + 192 + + + 193 + + + 194 +++ ++ ++ 195 ++ + + 196 + + + 197 + + + 198 ++ + + 199 + + + 200 ++ ++ + 201 ++ ++ + 202 + + + 203 + + + 204 ++ ++ + 205 + + + 206 + + + 207 + + + 208 + + − 209 + + − 210 + + − 211 + + − 212 + − − 213 + − − 214 + − − 215 + − − 216 + + − 217 + + − 218 + + − 219 ++ + − 220 ++ + − 221 + − − 222 + + − 223 + + − 224 + + − 225 ++ + − 226 + + − 227 + + − 228 + + − 229 + + − 230 + + − 231 + + − 232 ++ + − 233 + + − 234 + − − 235 + + − 236 + + − 237 ++ + − 238 + + − 239 ++ + − 240 + + − 241 + + − 242 + + − 243 + + − 244 + + − 245 + + − 246 ++ + − 247 + + − 248 + + − 249 + − − 250 + − − 251 ++ + − 252 + + − 253 + + − 254 + − − 255 + + − 256 + + − 257 + + − 258 + + − 259 + + − 260 + + − 261 + + − 262 + + − 263 ++ + − 264 + + − 265 + + − 266 + + − 267 + + − 268 + + − 269 + + − 270 + + − 271 + + − 272 + + − 273 + + − 274 + + − 275 + − − 276 + + − 277 ++ + − 278 ++ − − 279 + + − 280 + + − 281 + + − 282 ++ + − 283 + − − 284 + + − 285 + + − 286 + + − 287 + − − 288 + + − 289 + + − 290 + + − 291 + + − 292 + + − 293 + + − 294 + + − 295 ++ + − 296 + + − 297 + + − 298 + + − 299 + + − 300 + + − 301 + + − 302 + + − 303 + + − 304 + + − 305 + + − 306 + + − 307 + + − 308 + + − 309 + + − 310 + + − 311 + − − 312 ++ − − 313 + + − 314 + + − 315 + − − 316 + + − 317 + + − 318 + − − 319 + + − 320 + + − 321 + + − 322 + + − 323 + + − 324 + + − 325 + + − 326 ++ + − 327 + + − 328 + − − 329 ++ + − 330 + + − 331 + + − 332 + + − 333 + + − 334 ++ + − 335 ++ − − 336 + + − 337 + + − 338 + + − 339 + + − 340 + + − 341 + + − 342 + + − 343 + + − 344 + + − 345 + + − 346 + + − 347 + + − 348 + + − 349 + + − 350 + + − 351 + + −

VIII. Other Embodiments

It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. 

What is claimed is:
 1. A method of modulating a sodium ion channel comprising the step of contacting said sodium ion channel with a compound of formula I:

or a pharmaceutically acceptable salt thereof; wherein: Each X is defined by —Z^(A)R₆, wherein each Z^(A) is independently a bond or an optionally substituted branched or straight C₁₋₆ aliphatic chain wherein up to two carbon units of Z^(A) are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR^(A)—, —CONR^(A)NR^(A)—, —CO₂—, —OCO—, —NR^(A)CO₂—, —O—, —NR^(A)CONR^(A)—, —OCONR^(A)—, —NR^(A)NR^(A), —NR^(A)NR^(A)CO—, —NR^(A)CO—, —S—, —SO—, —SO₂—, —NR^(A)—, —SO₂NR^(A)—, —NR^(A)SO₂—, or —NR^(A)SO₂NR^(A)—; Each R₆ is independently R^(A), halo, —OH, —NH₂, —NO₂, —CN, —CF₃, or —OCF₃; Each R^(A) is independently hydrogen, an optionally substituted C₁₋₈ aliphatic group; a 3-8 membered optionally substituted fully saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an 8-12 membered optionally substituted fully saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R^(A) are taken together with the atom(s) to which they are attached to form an optionally substituted 3-12 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each n is 1-4; Each R₁ and R₂ is defined by —Z^(B)R₇, wherein each Z^(B) is independently a bond or an optionally substituted straight or branched C₁₋₆ aliphatic chain wherein up to two carbon units of Z^(B) are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR^(B)—, —CONR^(B)NR^(B)—, CO₂—, —OCO—, —NR^(B)CO₂—, —O—, —NR^(B)CONR^(B)—, —OCONR^(B)—, —NR^(B)NR^(B), —NR^(B)NR^(B)CO—, —NR^(B)CO—, —S—, —SO—, —SO₂—, —NR^(B)—, —SO₂NR^(B)—, —NR^(B)SO₂—, or —NR^(B)SO₂NR^(B)—; Each R₇ is independently R^(B), halo, —OH, —NHC(NH)NH₂, —NH₂, —NO₂, —CN, —CF₃, or —OCF₃; Each R^(B) is independently hydrogen, an optionally substituted C₁₋₈ aliphatic group, an optionally substituted 3-8 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an optionally substituted 8-12 membered fully saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R^(B) are taken together with the atom(s) to which they are attached to form an optionally substituted 3-12 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R³ and R⁴ is defined by —Z^(C)R₈, wherein each —Z^(C) is independently a bond or an optionally substituted straight or branched C₁₋₆ aliphatic chain wherein up to two carbon units of Z^(C) are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR^(C)—, —CONR^(C)NR^(C)—, —CO₂—, —OCO—, —NR^(C)CO₂—, —O—, —NR^(C)CONR^(C)—, —OCONR^(C)—, —NR^(C)NR^(C), —NR^(C)NR^(C)CO—, —NR^(C)CO—, —S—, —SO—, —SO₂—, —NR^(C)—, —SO₂NR^(C)—, —NR^(C)SO₂—, or —NR^(C)SO₂NR^(C)—; Each R₈ is independently R^(C), halo, —OH, —NH₂, —NO₂, —CN, —CF₃, or —OCF₃; Each R^(C) is independently hydrogen, or an optionally substituted C₁₋₈ aliphatic group, an optionally substituted 3-8 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an optionally substituted 8-12 membered fully saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R^(C) are taken together with the atom(s) to which they are attached to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each of which is optionally substituted with 1 to 3 substituents; and Each Y is hydrogen or unsubstituted C₁₋₃ alkyl.
 2. The method of claim 1, wherein R₁ is an optionally substituted araliphatic, an optionally substituted heteroaraliphatic, an optionally substituted C₁₋₈ aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.
 3. The method of claim 2, wherein R₁ is an optionally substituted —C₁₋₃ aliphatic-aryl.
 4. The method of claim 3, wherein R₁ is a phenylmethyl, phenylethyl, or phenylpropyl, in which the aliphatic and phenyl portion are each optionally substituted with 1-3 substituents independently selected from halo, hydroxy, cyano, nitro, aliphatic, haloaliphatic, alkylamino, cycloaliphatic, heterocycloaliphatic, (heterocycloaliphatic)alkyl, aminocarbonyl, aryl, and heteroaryl.
 5. The method of claim 2, wherein R₁ is an optionally substituted aliphatic.
 6. The method of claim 5, wherein R₁ is isopropyl.
 7. The method of claim 2, wherein R₁ is an optionally substituted cycloaliphatic or an optionally substituted heterocycloaliphatic.
 8. The method of claim 2, wherein R₁ is an optionally substituted aryl or an optionally substituted heteroaryl.
 9. The method of claim 2, wherein R₂ is hydrogen, an optionally substituted aliphatic, or an optionally substituted cycloaliphatic.
 10. The method of claim 9, wherein R₁ is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted araliphatic, or optionally substituted heteroaraliphatic.
 11. The method of claim 1, wherein R₁, R₂, and the nitrogen atom to which they are attached form an optionally substituted 4-12 membered fully saturated or partially unsaturated monocyclic or bicyclic ring including 1-3 heteroatoms.
 12. The method of claim 11, wherein R₁, R₂, and the nitrogen atom to which they are attached form a morpholinyl, piperadinyl, piperazinyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, imidazolidinyl, pyrazolyl, pyrazolidinyl, thiomorpholinyl, or 3,4-dihydro-benzo[b][1,4]oxazine, each of which is optionally substituted with 1-3 substituents selected from alkylcarbonyl, halo, cyano, hydroxy, an optionally substituted C₁₋₅ aliphatic, cycloaliphatic, heterocycloaliphatic, alkoxy, alkoxycarbonyl, alkylaminocarbonyl, aralkyl and heteroaralkyl.
 13. The method of claim 1, wherein, R₃, R₄ and the nitrogen atom to which they are attached form a 4-8 membered saturated or partially unsaturated monocyclic or bicyclic heterocycloaliphatic, or an optionally substituted 8-12 membered bicyclic heteroaryl, each of which includes 1-3 heteroatoms selected from N, O, and S.
 14. The method of claim 13, wherein R₃, R₄ and the nitrogen atom to which they are attached form a morpholinyl, thiomorpholinyl, piperadinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, imidazolinyl, a fully saturated or partially unsaturated bicyclic heterocycloaliphatic having 1-3 heteroatoms selected from N, O, and S, each of which is optionally substituted with 1-3 of alkylcarbonyl, halo, cyano, hydroxy, an optionally substituted C₁₋₅ aliphatic, cycloaliphatic, heterocycloaliphatic, alkoxy, alkoxycarbonyl, alkylaminocarbonyl, aralkyl and heteroaralkyl.
 15. The method of claim 1, wherein R₃ is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloaliphatic, an optionally substituted heterocycloalipahtic, or an optionally substituted C₁₋₈ aliphatic.
 16. The method of claim 16, wherein R₃ is an optionally substituted aryl.
 17. The method of claim 16, wherein R₃ is an optionally substituted aliphatic.
 18. The method of claim 16, wherein R₃ is an optionally substituted heteroaryl.
 19. The method of claim 1, wherein X is o-halo.
 20. A method of modulating a calcium or sodium ion channel comprising the step of contacting said calcium or sodium ion channel with a compound of formula Ia:

or a pharmaceutically acceptable salts thereof, wherein: Each X is defined by —Z^(A)R₆, wherein each Z^(A) is independently a bond or an optionally substituted branched or straight C₁₋₆ aliphatic chain wherein up to two carbon units of Z^(A) are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR^(A)—, —CONR^(A)NR^(A)—, —CO₂—, —OCO—, —NR^(A)CO₂—, —O—, —NR^(A)CONR^(A)—, —OCONR^(A)—, —NR^(A)NR^(A), —NR^(A)NR^(A)CO—, —NR^(A)CO—, —S—, —SO—, —SO₂—, —NR^(A)—, —SO₂NR^(A)—, NR^(A)SO₂—, or —NR^(A)SO₂NR^(A)—; Each R₆ is independently R^(A), halo, —OH, —NH₂, —NO₂, —CN, —CF₃, or —OCF₃; Each R^(A) is independently hydrogen, an optionally substituted C₁₋₈ aliphatic group; a 3-8 membered optionally substituted fully saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an 8-12 membered optionally substituted fully saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R^(A) are taken together with the atom(s) to which they are attached to form an optionally substituted 3-12 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each n is 1-4; Each R₁ and R₂ is defined by —Z^(B)R₇, wherein each Z^(B) is independently a bond or an optionally substituted straight or branched C₁₋₆ aliphatic chain wherein up to two carbon units of Z^(B) are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR^(B)—, —CONR^(B)NR^(B)—, —CO₂—, —OCO—, —NR^(B)CO₂—, —O—, —NR^(B)CONR^(B)—, —OCONR^(B)—, —NR^(B)NR^(B), —NR^(B)NR^(B)CO—, —NR^(B)CO—, —S—, —SO—, —SO₂—, —NR^(B)—, —SO₂NR^(B)—, —NR^(B)SO₂—, or —NR^(B)SO₂NR^(B)—; Each R₇ is independently R^(B), halo, —OH, —NHC(NH)NH₂, —NH₂, —NO₂, —CN, —CF₃, or —OCF₃; Each R^(B) is an optionally substituted C₁₋₈ aliphatic group, an optionally substituted 3-8 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an optionally substituted 8-12 membered fully saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R^(B) are taken together with the atoms) to which they are attached to form an optionally substituted 3-12 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R₃ and R₄ is defined by —Z^(C)R₈, wherein each Z^(C) is independently bond or an optionally substituted straight or branched C₁₋₆ aliphatic chain wherein up to two carbon units of Z^(C) are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR^(C)—, —CONR^(C)NR^(C)—, —CO₂—, —OCO—, —NR^(C)CO₂—, —O—, —NR^(C)CONR^(C)—, —OCONR^(C)—, —NR^(C)NR^(C), —NR^(C)NR^(C)CO—, —NR^(C)CO—, —S—, —SO—, —SO₂—, —NR^(C)—, —SO₂NR^(C)—, —NR^(C)SO₂—, or —NR^(C)SO₂NR^(C)—; Each R₈ is independently R^(C), halo, —OH, —NH₂, —NO₂, —CN, —CF₃, or —OCF₃; and Each R^(C) is independently hydrogen, or an optionally substituted C₁₋₈ aliphatic group, an optionally substituted 3-8 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an optionally substituted 8-12 membered fully saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R^(C) are taken together with the atom(s) to which they are attached to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocycle or bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each of which is optionally substituted with 1 to 3 substituents.
 21. The method of claim 20, wherein R₁ is an optionally substituted araliphatic, an optionally substituted heteroaraliphatic, an optionally substituted C₁₋₈ aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.
 22. The method of claim 21, wherein R₁ is an optionally substituted —C₁₋₃ aliphatic-aryl.
 23. The method of claim 21, wherein R₁ is an optionally substituted aliphatic.
 24. The method of claim 23, wherein R₁ is isopropyl.
 25. The method of claim 21, wherein R₁ is an optionally substituted cycloaliphatic or an optionally substituted heterocycloaliphatic.
 26. The method of claim 21, wherein R₁ is an optionally substituted aryl or an optionally substituted heteroaryl.
 27. The method of claim 21, wherein R₂ is hydrogen, an optionally substituted aliphatic, or an optionally substituted cycloaliphatic.
 28. The method of claim 27, wherein R₁ is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted araliphatic, or optionally substituted heteroaraliphatic.
 29. The method of claim 20, wherein R₁, R₂, and the nitrogen atom to which they are attached form an optionally substituted 4-12 membered fully saturated or partially unsaturated monocyclic or bicyclic ring including 1-3 heteroatoms.
 30. The method of claim 20, wherein, R₃, R₄ and the nitrogen atom to which they are attached form a 4-8 membered saturated or partially unsaturated monocyclic or bicyclic heterocycloaliphatic, or an optionally substituted 8-12 membered bicyclic heteroaryl, each of which includes 1-3 heteroatoms selected from N, O, and S.
 31. The method of claim 20, wherein R₃ is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloaliphatic, an optionally substituted heterocycloalipahtic, or an optionally substituted C₁₋₈ aliphatic.
 32. A method of modulating a sodium or calcium ion channel comprising the step of contacting said sodium ion channel with a compound selected from compound numbers 1-351 in Table
 1. 33. A compound of formula Ia:

or a pharmaceutically acceptable salt thereof, wherein: Each X is defined by —Z^(A)R₆, wherein each Z^(A) is independently a bond or an optionally substituted branched or straight C₁₋₆ aliphatic chain wherein up to two carbon units of Z^(A) are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR^(A)—, —CONR^(A)NR^(A)—, —CO₂—, —OCO—, —NR^(A)CO₂—, —O—, —NR^(A)CONR^(A)—, —OCONR^(A)—, —NR^(A)NR^(A), —NR^(A)NR^(A)CO—, —NR^(A)CO—, —S—, —SO—, —SO₂—, NR^(A)—, —SO₂NR^(A)—, —NR^(A)SO₂—, or —NR^(A)SO₂NR^(A)—; Each R₆ is independently R^(A), halo, —OH, —NH₂, —NO₂, —CN, —CF₃, or —OCF₃; Each R^(A) is independently hydrogen, an optionally substituted C₁₋₈ aliphatic group; a 3-8 membered optionally substituted fully saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an 8-12 membered optionally substituted fully saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R^(A) are taken together with the atom(s) to which they are attached to form an optionally substituted 3-12 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each n is 1-4; Each R₁ and R₂ is defined by —Z^(B)R₇, wherein each Z^(B) is independently a bond or an optionally substituted straight or branched C₁₋₆ aliphatic chain wherein up to two carbon units of Z^(B) are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR^(B)—, —CONR^(B)NR^(B)—, —CO₂—, —OCO—, —NR^(B)CO₂—, —O—, —NR^(B)CONR^(B)—, —OCONR^(B)—, —NR^(B)NR^(B), —NR^(B)NR^(B)CO—, —NR^(B)CO—, —S—, —SO—, —SO₂—, —NR^(B)—, —SO₂NR^(B)—, —NR^(B)SO₂—, or —NR^(B)SO₂NR^(B)—, or —NR^(B)SO₂NR^(B); Each R⁷ is independently R^(B), halo, —OH, —NHC(NH)NH₂, —NH₂, —NO₂, —CN, —CF₁, or —OCF₃; Each R^(B) is an optionally substituted C₁₋₈ aliphatic group, an optionally substituted 3-8 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an optionally substituted 8-12 membered fully saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R^(B) are taken together with the atom(s) to which they are attached to form an optionally substituted 3-12 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R₃ and R₄ is defined by —Z^(C)R₈, wherein each Z^(C) is independently a bond or an optionally substituted straight or branched C₁₋₆ aliphatic chain wherein up to two carbon units of Z^(C) are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR^(C)—, —CONR^(C)NR^(C)—, —CO₂—, —OCO—, —NR^(C)CO₂—, —O—, —NR^(C)CONR^(C)—, —OCONR^(C)—, —NR^(C)NR^(C), —NR^(C)NR^(C)CO—, —NR^(C)CO—, —S—, —SO—, —SO₂—, —NR^(C)—, —SO₂NR^(C)—, —NR^(C)SO₂—, or —NR^(C)SO₂NR^(C)—; Each R⁸ is independently R^(C), halo, —OH, —NH₂, —NO₂, —CN, —CF₃, or —OCF₃; and Each R^(C) is independently hydrogen, or an optionally substituted C₁₋₈ aliphatic group, an optionally substituted 3-8 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an optionally substituted 8-12 membered fully saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0.5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R^(C) are taken together with the atom(s) to which they are attached to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each of which is optionally substituted with 1 to 3 substituents, Provided that: when R₁ is alkyl, R₂ is not 3,5-bis-trifluoromethyl-phenyl-alkyl; when R₁ and R₂ together form pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted with —CH₃ or —CH₂CH₃, then X is not m-methyl, o-halo, p-aryl, or p-cyano; when R₁ or R₂ are aliphatic or alkoxyalkyl, then X is not m-methyl, o-halo, p-aryl, or p-cyano; and when R₁ is phenylmethyl optionally substituted with 1-2 —CH₃ groups or cycloaliphatic, and R₂ is unsubstituted methyl, ethyl, or isopropyl, then (1) R₃ together with R₄ form pyrrolidinyl, morpholinyl, piperidinyl optionally substituted with aliphatic, aminocarbonyl, or alkylcarbonyl, or one of R₃ or R₄ is phenylmethyl, methylfuranyl, or methoxypropyl; and (2) X is not m-methyl, p-aryl, o-halo or p-cyano.
 34. The compound of claim 33, wherein R₁ is an optionally substituted araliphatic, an optionally substituted heteroaraliphatic, an optionally substituted C₁₋₈ aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.
 35. The compound of claim 34, wherein R₁ is an optionally substituted —C₁₋₃ aliphatic-aryl.
 36. The compound of claim 35, wherein R₁ is a phenylmethyl, phenylethyl, or phenylpropyl, in which the aliphatic and phenyl portion are each optionally substituted with 1-3 substituents independently selected from halo, hydroxy, cyano, nitro, aliphatic, haloaliphatic, alkylamino, cycloaliphatic, heterocycloaliphatic, (heterocycloaliphatic)alkyl, aminocarbonyl, aryl, and heteroaryl.
 37. The compound of claim 35, wherein R₁ is a naphthylmethyl, naphthylethyl, naphthylpropyl, indenylmethyl, indenylethyl, or indenylpropyl, in which the aliphatic and the bicyclic aryl group are each optionally substituted with 1-3 of halo, hydroxy, cyano, nitro, aliphatic, haloaliphatic, alkylamino, cycloaliphatic, heterocycloaliphatic, (heterocycloaliphatic)alkyl, aminocarbonyl, aryl, heteroaryl, or combinations thereof.
 38. The compound of claim 35, wherein the aryl portion is an optionally substituted 2,3-dihydrobenzo[b][1,4]dioxinyl or an optionally substituted benzo[d][1,3]dioxolyl.
 39. The compound of claim 34, wherein R₁ is an optionally substituted 2,3-dihydrobenzofurylalkyl, an optionally substituted indolinylalkyl, an optionally substituted 2,3-dihydrobenzo[b][1,4]dioxinylalkyl, an optionally substituted benzo[d][1,3]dioxolylalkyl, an optionally substituted pyridinylalkyl, an optionally substituted isoindolinylalkyl, or an optionally substituted quinolinylalkyl.
 40. The compound of claim 34, wherein R₁ is methyl, ethyl, propyl, butyl, or isopropyl, each of which is optionally substituted with 1-2 substituents independently selected from halo, cyano, hydroxy, or optionally substituted aryl, aryloxy, alkylamino, heteroaryl, cycloaliphatic, or heterocycloaliphatic.
 41. The compound of claim 40, wherein R₁ is isopropyl.
 42. The compound of claim 34, wherein R₁ is an optionally substituted cycloaliphatic or an optionally substituted heterocycloaliphatic.
 43. The compound of claim 42, wherein R₁ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl, or bicyclo[2.2.1]heptyl, each of which is optionally substituted with 1-2 halo, hydroxy, aryl, heteroaryl, or combinations thereof.
 44. The compound of claim 34, wherein R₁ is an optionally substituted aryl or an optionally substituted heteroaryl.
 45. The compound of claim 34, wherein R₁ is phenyl, indenyl, dihydroindenyl, naphthyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, or benzo[d][1,3]dioxolyl, each of which is optionally substituted with 1-2 halo, hydroxy, cyano, or optionally substituted aliphatic, alkoxy, aryl, heteroaryl; or combinations thereof.
 46. The compound of claim 34, wherein R₂ is hydrogen, an optionally substituted aliphatic, or an optionally substituted cycloaliphatic.
 47. The compound of claim 46, wherein R₁ is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted araliphatic, or optionally substituted heteroaraliphatic.
 48. The compound of claim 33, wherein R₁ and R₂ are each independently selected from hydrogen, methyl, ethyl,


49. The compound of claim 33, wherein R₁, R₂, and the nitrogen atom to which they are attached form an optionally substituted 4-12 membered fully saturated or partially unsaturated monocycle or bicyclic ring including 1-3 heteroatoms.
 50. The compound of claim 49, wherein R₁, R₂, and the nitrogen atom to which they are attached form a morpholinyl, piperadinyl, piperazinyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, imidazolidinyl, pyrazolyl, pyrazolidinyl, thiomorpholinyl, or 3,4-dihydro-benzo[b][1,4]oxazine, each of which is optionally substituted with 1-3 substituents selected from, alkylcarbonyl, halo, cyano, hydroxy, an optionally substituted C₁₋₅ aliphatic, cycloaliphatic, heterocycloaliphatic, alkoxy, alkoxycarbonyl, alkylaminocarbonyl, aralkyl and heteroaralkyl.
 51. The compound of claim 33, wherein R₁, R₂ the nitrogen atom to which they are attached form a heterocycloaliphatic or a heterocycloaliphatic fused with phenyl selected from:


52. The compound of claim 33, wherein, R₃, R₄ and the nitrogen atom to which they are attached form a 4-8 membered saturated or partially unsaturated monocyclic or bicyclic heterocycloaliphatic, or an optionally substituted 8-12 membered bicycle heteroaryl, each of which includes 1-3 heteroatoms selected from N, O, and S.
 53. The compound of claim 52, wherein R₃, R₄ and the nitrogen atom to which they are attached form a morpholinyl, thiomorpholinyl, piperadinyl, piperizinyl, pyrrolidinyl, tetrahydrofuranyl, imidazolinyl, a fully saturated or partially unsaturated bicycle heterocycloaliphatic having 1-3 heteroatoms selected from N, O, and S, each of which is optionally substituted with 1-3 of alkylcarbonyl, halo, cyano, hydroxy, an optionally substituted C₁₋₅ aliphatic, cycloaliphatic, heterocycloaliphatic, alkoxy, alkoxycarbonyl, alkylaminocarbonyl, aralkyl and heteroaralkyl.
 54. The compound of claim 33, wherein R₃ is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloaliphatic, an optionally substituted heterocycloalipahtic, or an optionally substituted C₁₋₈ aliphatic.
 55. The compound of claim 54, wherein R₃ is phenyl, naphthyl or indenyl each optionally substituted with 1-3 of halo, cyano, hydroxy, alkoxy, alkoxycarbonyl, an optionally substituted C₁₋₆ aliphatic, aminocarbonyl, alkylaminocarbonyl, aryl, and heteroaryl.
 56. The compound of claim 54, wherein R₃ is alkyl optionally substituted with 1-2 of halo, cyano, —C(O)OH, hydroxy, cycloaliphatic, heterocycloaliphatic, optionally substituted aryl, alkoxy, haloalkylaryl, bicycloaliphatic, aryloxy, haloaryl, alkylamino, heteroaryl, cycloaliphatic, and heterocycloaliphaticpropyl.
 57. The compound of claim 54, wherein R₃ is an optionally substituted alkenyl.
 58. The compound of claim 54, wherein R₃ is an optionally substituted pyridinyl, pyrimidinyl, pyridazinyl, pyridinyl, isoindolinyl.
 59. The compound of claim 54, wherein R₃ is an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl, or bicyclo[22.1]heptyl.
 60. The compound of claim 33, wherein X is o-halo.
 61. The compound of claim 33, wherein R₃ and R₄ are each independently selected from hydrogen, methyl, ethyl,


62. The compound of claim 33, wherein R₃, R₄ the nitrogen atom to which they are attached form a heterocycloaliphatic or a heterocycloaliphatic fused with phenyl selected from:


63. The compound of claim 33, wherein R₁, R₂, R₃ and R₄ are each independently selected from hydrogen, methyl, ethyl,


64. The compound of claim 33, wherein R₁, R₂ and the nitrogen atom to which they are attached, or R₃, R₄ and the nitrogen atom to which they are attached, form a heterocycloaliphatic or a heterocycloaliphatic fused with phenyl selected from:


65. The compound of claim 33, wherein Each R₃ or R₄ is heterocycloaliphatic, bicycloaryl, bicycloheteroaliphatic, bicycloheteroaryl, heterocycloalkenyl, cycloaliphatic, alkenyl, 5-membered heterocycloaliphatic, heteroaralkyl, or bicycloaralkyl, each of which is optionally substituted; One of R₃ and R₄ is hydrogen; R₃ or R₄ is alkyl substituted with cycloaliphatic, heteroaryl, heterocycloaliphatic, cyano, alkoxycarbonyl, carboxy, guanidinylalkyl, bicycloaryl, halo, or alkoxy; or R₃ together with R₄ form a ring system selected from thiomorpholinyl, bicycloheteroaryl, bicyclic heterocycloaliphatic, 5-membered heterocycloaliphatic, and 6-membered heterocycloalkenyl; Provided that: when R₁ and R₂ together form pyrrolidinyl, morpholinyl, piperidinyl, each optionally substituted with —CH₃ or —CH₂CH₃, then X is not one selected from m-methyl, o-halo, p-aryl, and p-cyano; when R₁ and R₂ are aliphatic or alkoxyalkyl, then X is not one selected from m-methyl, o-halo, p-aryl, and p-cyano; and when R₁ is phenylmethyl optionally substituted with 1-2 —CH₃ groups or cycloaliphatic, and R₂ is one selected from unsubstituted methyl, ethyl, and isopropyl, then R₃ together with R₄ form pyrrolidinyl, morpholinyl, piperidinyl optionally substituted with aliphatic, or aminocarbonyl, or alkylcarbonyl, or R₃ or R₄ is phenylmethyl, methylfuranyl, or methoxypropyl, and X is not o-halo or p-cyano.
 66. A compound selected from compound numbers 1-207 from Table
 2. 67. A pharmaceutical composition, comprising a compound as in any of claims 32-66 and a pharmaceutically acceptable carrier. 